The present invention relates to amino alcohol derivatives having excellent immune suppression activity, pharmacologically acceptable salts thereof, esters thereof or other derivatives thereof; to pharmacological compositions containing said compound as an active ingredient; to the use of said compounds in the preparation of said pharmaceutical compositions; and to methods for prevention or treatment of autoimmune diseases which comprise administering a pharmacologically effective amount of said compound to warm blooded animals in need of such prevention of treatment.
In another aspect, the present invention relates to optically active novel amino alcohol derivatives (particularly, optically active 4,4-disubstiuted oxazolidin-2-one derivatives), which are useful synthetic intermediates for the preparation of said amino alcohol derivatives or other medicaments.
In yet another aspect the present invention relates to a novel processes for the excellent selective preparation of oily active 2-substituted 2-amino-1,3-propanediol mono-ester derivatives, which are useful synthetic intermediates for the preparation of said amino alcohol derivatives in optically active form.
Steroids or antiinflammatory drugs have been used as therapeutic agents for inflammatory responses caused by normal immunological responses in diseases related to the immune system such as rheumatoid arthritis and other autoimmune diseases. However, these agents are agents that improve the symptoms, but they do not provide treatment of the causes.
Although abnormal immunological responses have also been reported to contribute to the pathogenesis of diabetes mellits and nephritis [Kidney International, 51, 94 (1997); Journal of Immunology, 157, 4691 (1996)], no agents have ever been developed to improve the abnormal immunological responses.
On the other had, development of immune suppressors is important for prevention of immunological rejection occurring in organ transplantation or for the prevention or therapy of autoimmune diseases. Nevertheless, well known immunosuppressors such as cyclosporin A (CsA) and tacrolimus (TRL) are known to cause renal toxicity or hepatotoxicity. Although steroids have been administered together with immunosuppressors in order to decrease such adverse effects of the immunosuppressors, the immunosuppressing effects could not be satisfactorily elicited without the adverse events.
From these backgrounds, many attempts have been made to find compounds exerting excellent immunosuppressing effects with low toxicity.
The following compounds are known as immunosuppressive agents:
(1) In the specification of WO94/08943 (EP627406) compounds of formula (a) are disclosed as immunosuppressive agents, 
wherein R is a straight or branched carbon chain which may have, in the chain, a group selected from the group consisting of a double bond, a triple bond, oxygen atom, sulfur atom xe2x80x94N(R6)xe2x80x94 (wherein R6 is a hydrogen atom), optionally substituted akylene, optionally substituted heteroarylene or the like, and which may be substituted, at the chain end thereof, by optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heteroaryl or the like; and R2, R3, R4, R5 are the same or different and each represent a hydrogen atom, an alkyl group or the like.
The compounds of formula (a) have two oxymethyl groups (xe2x80x94CH2OR4 and xe2x80x94CH2OR5) as essential groups. The compounds of the present invention, however, have a xe2x80x94CH2OR3 group and a lower alkyl group and are different from the compounds of formula (a) in these substituents.
In said specification no typical compounds similar to the compounds of formula (I) in the present invention are disclosed at all. Only the following two compounds of the compounds of formula (a) are highly similar in chemical structure to the compounds of formula (I) in the present invention:
Example 29 (FTY720) 
Example 293
(2) In the specification of WO96/06068 compounds of formula (b) are disclosed as immunosuppressive agents, 
wherein R1, R2 and R3 each are a hydrogen atom or the like; W is a hydrogen atom, an alkyl group or the like; Z is a single bond or an alkylene group; X is a hydrogen atom or an alkoxy group; Y is a hydrogen atom, an alkyl, alkoxy, acyl, acyloxy, amino, acylamino group or the like.
The compounds of formula (b) essentially have a phenyl group as a basic skeleton. The compounds of formula (I) in the present invention have a thiophene group instead of the phenyl group of compounds of formula (b) and are different from the compounds of formula (b) in the basic skeleton.
In said specification no typical compounds similar to the compounds of formula (I) in the present invention are disclosed at all. Only the following three compounds of the compounds of formula (b) are highly similar in chemical structure to the compounds of formula (I) in the present invention:
Example 26
Example 57
Example 87
(3) In the specification of WO98/45249 compounds of formula (c) are disclosed as immunosuppressive agents, 
wherein R1, R2, R3, R4 are the same or different and each represent a hydrogen atom or an acyl group. The compounds of formula (c) have two oxymethyl groups (xe2x80x94CH2OR3 and xe2x80x94CH2OR4) as essential substituent groups. The compounds of the present invention have a CH2OR3 group and a lower alkyl group and are different from the compounds of formula (a) in these substituents. The compounds of formula (c) have a phenyl group between xe2x80x94(CH2)2xe2x80x94 and xe2x80x94CO(CH2)4xe2x80x94 as a basic skeleton. The compounds of formula (I) in the present invention have a thiophene group instead of the phenyl group of the compounds of formula (c). The present compounds of formula (I) are also different from the compounds of formula (c) in the basic skeleton. The compounds of formula (c) have only a phenyl group at the end of xe2x80x94COxe2x80x94(CH2)4xe2x80x94 group. The compounds of formula (I) in the present invention may have a phenyl group, a cycloalkyl group or a heterocyclic group at the end of the molecule.
In said specification no typical compounds similar in chemical structure to the compounds of formula (I) in the present invention are disclosed at all. Only the following three compounds of the compounds of formula (c) are highly similar in chemical structure to the compounds of formula (I) in the present invention:
Example 1
Example 3
On the other hand, various optically active substituted amino acid and substituted amino alcohol derivatives (particularly xcex1-substituted amino acid and xcex1-substituted amino alcohol derivatives) exhibit biological activity, are partial components of natural products and pharmaceutical agents; and are important synthetic intermediates. For example, xcex1-methyl-xcex1-vinyl amino acids are useful as an amino acid decarboxylase inhibitor, xcex1-ethynyl-xcex1-methyl amino acids are useful as a glutamic acid decarboxylase inhibitor, ISP-1 (Myriocin), which is isolated from metabolites of Isalia sinclairii, has immune suppression activity; and Conagenine and the like participate in the regulation of immune response through T-cells. From these results, xcex1-substituted amino acid and amino alcohol derivatives are very interesting compounds as a partial component of natural products having biological activity, in the field of biochemistry and in the field of organic synthesis.
These xcex1-substituted amino acid and amino alcohol derivatives have an asymmetric center(s) and an efficient process for the preparation of one enantiomer thereof has been expected.
There are a few reports of processes for the preparation of optically active substituted amino acid and amino alcohol derivatives and a few reports of synthetic examples of optically active amino alcohol derivatives such as optically active 4,4-disubstituted oxazolizin-2-one derivatives, which are useful synthetic intermediates of optically active substituted amino acid and amino alcohol derivatives described hereinbefore. For example, there are reports by C. Cativiela et al., Tetrahedron: Asymmetry, 9, 3517 (1998) and Synthesis of Optically active xcex1-amino acids (Pergamon Press) R. M. Williams et al and the methods are largely classified into two groups for preparation of them. The one is a diasteroselective alkylation method using an assisting group for asymmetric synthesis, a typical example being a method described by Seebach in Helv. Chim. Acta., 71, 224 (1988) or the synthesis of xcex1-substituted serine derivatives which are obtained by a highly diasteroselective aldol reaction using chiral bis-lactam ether carboxylic acid esters and Mg(II) and Sn(II) type Lewis acids described by Nagao and Sano et al. in Tetrahedron Lett., 36, 2097 (1995) and Tetrahedron Lett., 36, 4101 (1995). The other one is a synthesis of xcex1-substituted serine derivatives which are obtained by enantioselective enzymatic hydrolysis of prochiral "sgr"-symmetry diester compounds (xcex1-substituted-xcex1-protected malonic acid diesters) and is described by Nagao, Tamai et al, in Chemistry Lett., 239 (1989) and Chemistry Lett., 2381 (1994).
The former method has multi-step reactions and needs a stoichiometric asymmetric source. The latter method has a reduction step and cannot be used when a compound has a group unstable under reduction conditions.
There are some reports described hereinbefore but, however the practically useful methods are limited. In general, one enantiomer is optically resolved from a racemic mixture. In this case them is a problem that the total yield of the desired compound is low.
The present inventors have performed painstaking research to completed these objectives, and found that the amino alcohol derivatives (I) of the present invention exert an excellent immunosuppressive effect with low toxicity and are useful as therapeutic agents for autoimmune disease such as systemic lupus erythematosus, rheumatoid arthritis, polymyositis, dermatomyositis, Behcet""s syndrome, Chron disease, ulcerative colitis, autoimmune hepatitis, aplastic anemia, scleoderma, idiopathic thromboytopenic purpura, autoimmune hemolytic anemia, multiple sclerosis, autoimmune bullosis, vulgarity psoriasis, vasculitis syndrome, Wegener""s granuloma, uveitis, cryptogenic fibrosing alveolitis, Goodpasture""s syndrome, sarcoidosis, allergic granulomatous angitis, bronchial asthma, myocarditis, cardiomyopathy, aortic arch syndrome, myocardial postinfarction syndrome, primary pulmonary hypertension, minimal change nephrotic syndrome, membranous nephropathy, membmnopmliferative glomerulonephritis, focal glomerular sclerosis, crescent glomerulonephritis, myasthenia gavis, inflammatory neuropathy, atopic dermatitis, chronic actinic dermatitis, acute polyarthritis, Sydenhan chorea disease, progressive systemic sclerosis, adult onset type diabetes mellitus, insulin dependent diabetes mellitus, juvenile diabetes, atherosclerosis, glomerular nephritis, tuburointerstitial nephritis, primary biliary cirrhosis, primary sclerosis cholangitis, fulminant hepatic failure, viral hepatitis, GVHD, immunological rejection following organ transplantation, contact dermatitis, sepsis or other immunology related diseases, and completed the present invention.
The present invention provides amino alcohol derivatives which exhibit low toxicity and excellent immune suppression activity, pharmacologically acceptable salts thereof, esters thereof or other derivatives thereof.
In another aspect, the present invention provides pharmaceutical compositions containing said amino alcohol derivatives, a pharmacologically acceptable salt thereof, an ester thereof, or other derivative thereof as an active ingredient; the use of said compounds in the preparation of said pharmaceutical compositions; or methods for prevention or treatment of the diseases described hereinbefore such as autoimmune diseases and the like, which comprise administering a pharmacologically effective amount of said compound to warm blooded animals (e.g. humans) in need of such prevention or treatment.
The inventors have made a great effort to solve the problems described hereinbefore about a process for the preparation of optically active amino alcohol derivatives and intermediates thereof. They have found that optically active novel amino alcohol derivatives of formulae (La) and (Lb) (especially 4,4-disubstituted oxazolizin-2-one derivatives) can be obtained more easily than by conventional methods and said derivatives are useful synthetic intermediates for the preparation of optically active substituted amino acid and substituted amino alcohol derivatives and medicaments.
In addition they have also made a great effort to find a process for the selective preparation of the optically active amino alcohol compounds of formulae (La) and (Lb). They found that optically active 2-substituted 2-amino-1,3-propanediol mono-ester derivatives of formulae (XLIVa) or (XLIVb) are useful intermediate for the preparation and said compounds of formulae (XLIVa) and (XLIVb) can easily be obtained from 2-substituted 2-amino-1,3-propanediol derivatives of formula (XLII) using carboxylic acid vinyl esters of formula (XLII) in the presence of lipase through selective acylation of one hydroxyl group in good yield.
(1) The present invention comprises amino alcohol derivatives of the following formula (I), pharmacologically acceptable salts thereof, esters thereof or other derivatives thereof: 
wherein
R1 and R2 are the same or different and each represents a hydrogen atom or an amino protecting group;
R3 represents a hydrogen atom or a hydroxy protecting group;
R4 represents a lower alkyl group;
n represents an integer from 1 to 6;
X represents an ethylene group, a vinylene group, an ethynylene group, a group of formula xe2x80x94Dxe2x80x94CH2xe2x80x94 (wherein D represents a carbonyl group, a group of formula xe2x80x94CH(OH)xe2x80x94, an oxygen atom, a sulfur atom, or a nitro atom), an aryl group, or an aryl group substituted with 1 to 3 substituents selected from substituent group a;
Y represent a single bond, a C1-C10 alkylene group, a C1-C10 alkylene group substituted with 1 to 3 substituents selected from substituent groups a and b, a C1-C10 alkylene group which has an oxygen atom or a sulfur atom in said carbon chain or at the end of said carbon chain, or a C1-C10 alkylene group which is substituted with 1 to 3 substituents selected from substituent groups a and b and has an oxygen atom or a sulfur atom in said carbon chain or at the end of said carbon chain;
R5 represents a hydrogen atom, a cycloalkyl group, an aryl group, a heterocyclic group, a cycloalkyl group substituted with 1 to 3 substituents selected from substituent groups a and b, an aryl group substituted with 1 to 3 substituents selected from substituent groups a and b, or a heterocyclic group substituted with 1 to 3 substituents selected from substituent groups a and b;
R6 and R7 are the same or different and each represents a hydrogen atom or a group selected from substituent group a;
with the proviso that when R5 is a hydrogen atom, Y is not a single bond or a straight C1-C10 alkylene group;
substituent group a consists of a halogen atom, a lower alkyl group, a halognated lower alkyl group, a lower alkoxy group, a lower alkylthio group, a carboxyl group, a lower alkoxycarbonyl group, a hydroxyl group, a lower aliphatic acyl group, an amino group, a mono lower alkylamino group, a di lower alkylamino group, a lower aliphatic acylamino group, a cyano group, and a nitro group;
substituent group b consists of a cycloalkyl group, an aryl group, a heterocyclic group, a cycloalkyl group substituted with 1 to 3 substituents selected from substituent group a, an aryl group substituted with 1 to 3 substituents selected from substituent group a, and a hetrocyclic group substituted with 1 to 3 substituents selected from substituent group a.
Among these compounds described in (1), preferred compounds include:
(2) a compound according to (1) wherein said compound has a formula (Ia), a pharmacologically acceptable salt thereof, an ester thereof or other derivative thereof; 
(3) a compound according to (1) wherein said compound has a formula (Ib), a pharmacologically acceptable salt thereof an ester thereof or other derivative thereof; 
(4) a compound according to any one of (1) to (3) wherein R1 and R2 are the same or different and each is a hydrogen atom, a lower alkoxycarbonyl group, an aralkyloxycarbonyl group, or an arakyloxycarbonyl group substituted with 1 to 3 substituents selected from substituent group a, or a pharmacologically acceptable salt thereof;
(5) a compound according to any one of (1) to (3) wherein each of R1 and R2 is a hydrogen atom, or a pharmacologically acceptable salt thereof;
(6) a compound according to any one of (1) to (5) wherein R3 is a hydrogen atom, a lower alkyl group, a lower aliphatic acyl group, an aromatic acyl group or an aromatic acyl group substituted with 1 to 3 substituents selected from substituent group a, or a pharmacologically acceptable salt thereof;
(7) a compound according to any one of (1) to (5) wherein R3 is a hydrogen atom, or a pharmacologically acceptable salt thereof;
(8) a compound according to any one of (1) to (7) wherein R4 is a C1-C4 alkyl group, or a pharmacologically acceptable salt thereof;
(9) a compound according to any one of (1) to (7) wherein R4 is a C1-C2 alkyl group, or a pharmacologically acceptable salt thereof;
(10) a compound according to any one of (1) to (7) wherein R4 is a methyl group, or a pharmacologically acceptable salt thereof;
(11) a compound according to any one of (1) to (10) wherein n is 2 or 3, or a pharmacologically acceptable salt thereof;
(12) a compound according to any one of (1) to (10) wherein n is 2, or a pharmacologically acceptable salt thereof;
(13) a compound according to any one of (1) to (12) wherein X is an ethylene group, an ethynylene group, an aryl group, or an aryl group substituted with 1 to 3 substituents selected from substituent group a, or a pharmacologically acceptable salt thereof;
(14) a compound according to any one of (1) to (12) wherein X is an ethylene group, or a pharmacologically acceptable salt thereof;
(15) a compound according to any one of (1) to (12) wherein X is an ethynylene group, or a pharmacologically acceptable salt thereof;
(16) a compound according to any one of (1) to (12) wherein X is a group of formula xe2x80x94Dxe2x80x94CH2xe2x80x94, or a pharmacologically acceptable salt thereof;
(17) a compound according to any one of (1) to (12) wherein X is a group of formula xe2x80x94Dxe2x80x94CH2xe2x80x94 (wherein D represents a carbonyl group or a group of formula xe2x80x94CH(OH)xe2x80x94), or a pharmacologically acceptable salt thereof;
(18) a compound according to any one of (1) to (17) wherein Y is a C1-C10 alkylene group, or a C1-C10 alkylene group substituted with 1 to 3 substituents selected from substituent groups a and b, or a pharmacologically acceptable salt thereof;
(19) a compound according to any one of (1) to (17) wherein Y is a C1-C6 alkylene group, or a C1-C6 alkylene group substituted with 1 to 3 substituents selected from substituent groups a and b, or a pharmacologically acceptable salt thereof;
(20) a compound according to any one of (1) to (17) wherein Y is an ethylene group, a trimethylene group, a tetramethylene group, an ethylene group substituted with 1 to 3 substituents selected from substituent groups a and b, a trimethylene group substituted with 1 to 3 substituents selected from substituent groups a and b, or a tetramethylene group substituted with 1 to 3 substituents selected from substituent groups a and b, or a pharmacologically acceptable salt thereof;
(21) a compound according to any one of (1) to (17) wherein Y is an ethylene group, a trimethylene group, or a tetramethylene group, or a pharmacologically acceptable salt thereof;
(22) a compound according to any one of (1) to (17) wherein Y is an ethylene group or a trimethylene group, or a pharmacologically acceptable salt thereof;
(23) a compound according to any one of (1) to (17) wherein Y is a C1-C10 alkylene group which has an oxygen atom or a sulfur atom in said carbon chain or at the end of said carbon chain, or a C1-C10 alkylene group which is substituted with 1 to 3 substituents selected from substituent groups a and b and has an oxygen atom or a sulfur atom in said carbon chain or at the end of said carbon chain, or a pharmacologically acceptable salt thereof;
(24) a compound according to any one of (1) to (17) wherein Y is a C1-C10 alkylene group which has an oxygen atom or a sulfur atom in said carbon chain or at the end of said carbon chain, or a pharmacologically acceptable salt thereof;
(25) a compound according to any one of (1) to (17) wherein Y is a C1-C10 alkylene group which has an oxygen atom in said carbon chain or at the end of said carbon chain, or a pharmacologically acceptable salt thereof;
(26) a compound according to any one of (1) to (17) wherein Y is a C1-C6 alkylene group which has an oxygen atom in said carbon chain or at the end of said carbon chain, or a pharmacologically acceptable salt thereof;
(27) a compound according to any one of (1) to (17) wherein Y is a group of formula xe2x80x94Oxe2x80x94CH2xe2x80x94, xe2x80x94O(CH2)2xe2x80x94, xe2x80x94(CH2)3xe2x80x94, xe2x80x94CH2Oxe2x80x94, xe2x80x94(CH2)2xe2x80x94Oxe2x80x94, or xe2x80x94(CH2)3Oxe2x80x94, or a pharmacologically acceptable salt thereof;
(28) a compound according to any one of (1) to (17) wherein Y is a group of formula xe2x80x94CH2Oxe2x80x94, or a pharmacologically acceptable salt thereof;
(29) a compound according to any one of (1) to (17) wherein Y is a group of formula xe2x80x94Oxe2x80x94(CH2)2xe2x80x94 or xe2x80x94(CH2)2xe2x80x94Oxe2x80x94, or a pharmacologically acceptable salt thereof;
(30) a compound according to any one of (1) to (29) wherein R5 is a hydrogen atom, or a pharmacologically acceptable salt thereof;
(31) a compound according to any one of (1) to (29) wherein R5 is a cycloalkyl group, a heterocyclic group, a cycloalkyl group substituted with 1 to 3 substituents selected from substituent groups a and b, or a heterocyclic group substituted with 1 to 3 substituents selected from substituent groups a and b, or a pharmacologically acceptable salt thereof;
(32) a compound according to any one of (1) to (29) wherein R5 is a cycloalkyl group or a cycloalkyl group substituted with 1 to 3 substituents selected from substituent groups a and b, or a pharmacologically acceptable salt thereof;
(33) a compound according to any one of (1) to (29) wherein R5 is a cycloalkyl group, or a pharmacologically acceptable salt thereof;
(34) a compound according to any one of (1) to (29) wherein R5 is a cyclohexyl group, or a pharmacologically acceptable salt thereof;
(35) a compound according to any one of (1) to (29) wherein R5 is an aryl group or an aryl group substituted with 1 to 3 substituents selected from substituent groups a and b, or a pharmacologically acceptable salt thereof;
(36) a compound according to any one of (1) to (29) wherein R5 is an aryl group or an aryl group substituted with 1 to 3 substituents (said substituent is selected from the group consisting of a halogen atom, a lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group, a lower alkylthio group and a lower aliphatic acyl group), or a pharmacologically acceptable salt thereof;
(37) a compound according to any one of (1) to (29) wherein R5 is an aryl group or an aryl group substituted with 1 to 3 substituents (said substituent is selected from the group consisting of a halogen atom, a lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group, and a lower aliphatic acyl group), or a pharmacologically acceptable salt thereof;
(38) a compound according to any one of (1) to (29) wherein R5 is a phenyl group or a phenyl group substituted with 1 to 3 substituents (said substituent is selected from the group consisting of a halogen atom, a lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group, and a lower aliphatic acyl group), or a pharmacologically acceptable salt thereof;
(39) a compound according to any one of (1) to (29) wherein R5 is a phenyl group or a phenyl group substituted with 1 to 3 substituents (said substituent is selected from the group consisting of a fluorine atom, a chlorine atom, a methyl, trifluoromethyl, methoxy, and acetyl group), or a pharmacologically acceptable salt thereof;
(40) a compound according to any one of (1) to (29) wherein R5 is a phenyl, 3-fluorophenyl, 4-fluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 3-methylphenyl, 4-methylphenyl, 3,4-dimethylphenyl, 3,5-dimethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3,4-ditrifluoromethylphenyl, 3,5-ditrifluoromethylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 3-acetylphenyl, or 4-acetylphenyl, or a pharmacologically acceptable salt thereof;
(41) a compound according to any one of (1) to (40) wherein R6 and R7 are the same or different and each is a hydrogen atom, a halogen atom, a lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group or a lower alkylthio group, or a pharmacologically acceptable salt thereof;
(42) a compound according to any one of (1) to (40) wherein each of R6 and R7 is a hydrogen atom, or a pharmacologically acceptable salt thereof;
(43) a compound according to (1) wherein said compound is selected the following compounds, a pharmacologically acceptable salt thereof, an ester thereof or other derivative thereof:
2-amino-2-methyl-4-[5-(6-cyclohexylhexyl)thiophen-2-yl]butan-1-ol,
2-amino-2-methyl-4-[5-(5-cyclohexylpentyl)thiophen-2-yl]butan-1-ol,
2-amino-2-methyl-4-[5-(4-cyclohexylbutyl)thiophen-2-yl]butan-1-ol,
2-amino-2-methyl-4-[5-(6-cyclohexylhex-1-ynyl)thiophen-2-yl]butan-1-ol,
2-amino-2-methyl-4-[5-(5-cyclohexylpent-1-ynyl)thiophen-2-yl]butan-1-ol,
2-amino-2-methyl-4-[5-(4-cyclohexylbut-1-ynyl)thiophen-2-yl]butan-1-ol,
2-amino-2-methyl-4-[5-(6-cyclohexylhexanoyl)thiophen-2-yl]butan-1-ol,
2-amino-2-methyl-4-[5-(5-cyclohexylpentanoyl)thiophen-2-yl]butan-1-ol,
2-amino-2-methyl-4-[5-(4-cyclohexylbutanoyl)thiophen-2-yl]butan-1-ol,
2-amino-2-ethyl-4-[5-(6-cyclohexylhexyl)thiophen-2-yl]butan-1-ol,
2-amino-2-ethyl-4-[5-(5-cyclohexylpentyl)thiophen-2-yl]butan-1-ol,
2-amino-2-ethyl-4-[5-(4-cyclohexylbutyl)thiophen-2-yl]butan-1-ol,
2-amino-2-ethyl-4-[5-(6-cyclohexylhex-1-ynyl)thiophen-2-yl]butan-1-ol,
2-amino-2-ethyl-4-[5-(5-cyclohexylpent-1-ynyl)thiophen-2-yl]butan-1-ol,
2-amino-2-ethyl-4-[5-(4-cyclohexylbut-1-ynyl)thiophen-2-yl]butan-1-ol,
2-amino-2-ethyl-4-[5-(6-cyclohexylhexanoyl)thiophen-2-yl]butan-1-ol,
2-amino-2-ethyl-4-[5-(5-cyclohexylpentanoyl)thiophen-2-yl]butan-1-ol,
2-amino-2-ethyl-4-[5-(4-cyclohexylbutanoyl)thiophen-2-yl]butan-1-ol,
2-amino-2-methyl-4-[5-(6-phenylhexyl)thiophen-2-yl]butan-1-ol,
2-amino-2-methyl-4-[5-(5-phenylpentyl)thiophen-2-yl]butan-1-ol,
2-amino-2-methyl-4-[5-(4-phenylbutyl)thiophen-2-yl]butan-1-ol,
2-amino-2-methyl-4-[5-(6-phenylhex-1-ynyl)thiophen-2-yl]butan-1-ol,
2-amino-2-methyl-4-[5-(5-phenylpent-1-ynyl)thiophen-2-yl]butan-1-ol,
2-amino-2-methyl-4-[5-(4-phenylbut-1-ynyl)thiophen-2-yl]butan-1-ol,
2-amino-2-methyl-4-[5-(6-phenylhexanoyl)thiophen-2-yl]butan-1-ol,
2-amino-2-methyl-4-[5-(5-phenylpentanoyl)thiophen-2-yl]butan-1-ol,
2-amino-2-methyl-4-[5-(4-phenylbutanoyl)thiophen-2-yl]butan-1-ol,
2-amino-2-methyl-4-[5-(5-cyclohexyloxypent-1-ynyl)thiophen-2-yl]butan-1-ol,
2-amino-2-methyl-4-[5-(4-cyclohexyloxybut-1-ynyl)thiophen-2-yl]butan-1-ol,
2-amino-2-methyl-4-[5-(3-cyclohexyloxypropynyl)thiophen-2-yl]butan-1-ol,
2-amino-2-methyl-4-[5-(5-cyclohexyloxypentyl)thiophen-2-yl]butan-1-ol,
2-amino-2-methyl-4-[5-(4-cyclohexyloxybutyl)thiophen-2-yl]butan-1-ol,
2-amino-2-methyl-4-[5-(3-cyclohexyloxypropyl)thiophen-2-yl]butan-1-ol,
2-amino-2-methyl-4-[5-(5-cyclohexyloxypentanoyl)thiophen-2-yl]butan-1-ol,
2-amino-2-methyl-4-[5-(4-cyclohexyloxybutanoyl)thiophen-2-yl]butan-1-ol,
2-amino-2-methyl-4-[5-(3-cyclohexyloxypropanoyl)thiophen-2-yl]butan-1-ol,
2-amino-2-methyl-4-[5-(5-phenoxypent-1-ynyl)thiophen-2-yl]butan-1-ol,
2-amino-2-methyl-4-[5-(4-phenoxybut-1-ynyl)thiophen-2-yl]butan-1-ol,
2-amino-2-methyl-4-[5-(3-phenoxypropynyl)thiophen-2-yl]butan-1-ol,
2-amino-2-methyl-4-[5-(5-phenoxypentyl)thiophen-2-yl]butan-1-ol,
2-amino-2-methyl-4-[5-(4-phenoxybutyl)thiophen-2-yl]butan-1-ol,
2-amino-2-methyl-4-[5-(3-phenoxypropyl)thiophen-2-yl]butan-1-ol,
2-amino-2-methyl-4-[5-(5-phenoxypentanoyl)thiophen-2-yl]butan-1-ol,
2-amino-2-methyl-4-[5-(4-phenoxybutanoyl)thiophen-2-yl]butan-1-ol,
2-amino-2-methyl-4-[5-(3-phenoxypropanoyl)thiophen-2-yl]butane-1-ol,
2-amino-2-methyl-4-[5-(4-benzyloxyphenyl)thiophen-2-yl]butan-1-ol,
2-amino-2-methyl-4-[5-(4-cyclohexylmethoxyphenyl)thiophen-2-yl]butan-1-ol,
2-amino-2-methyl-4-[5-(4-cyclohexylethoxyphenyl)thiophen-2-yl]butan-1-ol,
2-amino-2-methyl-4-[5-(3-cyclohexylmethoxypropynyl)thiophen-2-yl]butan-1-ol,
2-amino-2-methyl-4-[5-(3-cyclohexylmethoxypropyl)thiophen-2-yl]butan-1-ol, and
2-amino-2-methyl-4-[5-(3-cyclohexylmethoxypropynyl)thiophen-2-yl]butan-1-ol.
(44) a compound according to (1) wherein said compound is selected the following compounds, a pharmacologically acceptable salt thereof, an ester thereof or other derivative thereof:
2-amino-2-methyl-4-[5-(4-cyclohexylbutyl)thiophen-2-yl]butan-1-ol,
2-amino-2-methyl-4-[5-(5-cyclohexylpentyl)thiophen-2-yl]butan-1-ol,
2-amino-2-methyl-4-[5-(5-phenylpentyl)thiophen-2-yl]butan-1-ol,
2-amino-2-methyl-4-[5-(4-cyclohexyloxybutyl)thiophen-2-yl]butan-1-ol,
2-amino-2-methyl-4-{5-[4-(4-fluorophenoxy)butyl]thiophen-2-yl}butan-1-ol,
2-amino-2-methyl-4-{5-[4-(4-methoxyphenoxy)butyl]thiophen-2-yl}butan-1-ol,
2-amino-2-methyl-4-[5-(4-benzyloxybutyl)thiophen-2-yl]butan-1-ol,
2-amino-2-methyl-4-[5-(4-cyclohexylbut-1-ynyl)thiophen-2-yl]butan-1-ol,
2-amino-2-methyl-4-[5-(4-phenylbut-1-ynyl)thiophen-2yl]butan-1-ol,
2-amino-2-methyl-4-[5-(5-cyclohexylpent-1-ynyl)thiophen-2-yl]butan-1-ol,
2-amino-2-methyl-4-[5-(5-phenylpent-1-ynyl)thiophen-2-yl]butan-1-ol,
2-amino-2-methyl-4-{5-[5-(4-fluorophenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol,
2-amino-2-methyl-4-{5-[5-(4-methoxyphenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol,
2-amino-2-methyl-4-{5-[3-(4-methylcyclohexyloxy)propynyl]thiophon-2-yl}butan-1-ol,
2-amino-2-methyl-4-{5-[3-(4-methylphenoxy)propynyl]thiophen-2-yl}butan-1-ol,
2-amino-2-methyl-4-{5-[3-(4-ethylphenoxy)propynyl]thiophen-2-yl}butan-1-ol,
2-amino-2-methyl-4-{5-[3-(4-methylthiophenoxy)propynyl]thiophen-2-yl}butan-1-ol,
2-amino-2-methyl-4-[5-(4-cyclohexyloxybut-1-ynyl)thiophen-2-yl]butan-1-ol,
2-amino-2-methyl-4-{5-[4-(4-fluorophenoxy)but-1-ynyl]thiophen-2-yl}butan-1-ol,
2-amino-2-methyl-4-{5-[4-(4-methylphenoxy)but-1-ynyl]thiophen-2-yl}butan-1-ol,
2-amino-2-methyl-4-[5-(3-cyclohexylmethoxypropynyl)thiophen-2-yl]butan-1-ol,
2-amino-2-methyl-4-[5-(4-phenylmethoxybut-1-ynyl)thiophen-2-yl]butan-1-ol,
2-amino-2-methyl-4-[5-(4-cycohexylbutanoyl)thiophen-2-yl]butan-1-ol,
2-amino-2-methyl-4-[5-(4-phenylbutanoyl)thiophen-2-yl]butan-1-ol,
2-amino-2-methyl-4-[5-(5-cyclohexylpentanoyl)thiophen-2-yl]butan-1-ol,
2-amino-2-methyl-4-[5-(5-phenylpentanoyl)thiophen-2-yl]butan l-ol,
2-amino-2-methyl-4-{5-[5-(4-fluorophenyl)pentanoyl]thiophen-2-yl}butan-1-ol,
2-amino-2-ethyl-4-[5-(5-cyclohexylpentyl)thiophen-2-yl]butan-1-ol,
2-amino-2-ethyl-4-[5-(5-cyclohexylpent-1-ynyl)thiophen-2-yl]butan-1-ol,
2-amino-2-ethyl-4-[5-(5-cyclohexylpentanoyl)thiophen-2-yl]butan-1-ol,
2-amino-2-methyl-4-{5-[3-(4-chlorophenoxy)propynyl]thiophen-2-yl}butan-1-ol,
2-amino-2-methyl-4-{5-[3-(3-methylphenoxy)propynyl]thiophen-2-yl}butan-1-ol,
2-amino-2-methyl-4-{5-[3-(3,4-dimethylphenoxy)propynyl]thiophen-2-yl}butan-1-ol,
2-amino-2-methyl-4-{5-[3-(3-methoxyphenoxy)propynyl]thiophen-2-yl}butan-1-ol,
2-amino-2-methyl-4-{5-[3-(3-dimethoxyphenoxy)propynyl]thiophen-2-yl}butan-1-ol,
2-amino-2-methyl-4-{5-[3-(3,5-dimethoxyphenoxy)propynyl]thiophen-2-yl}butan-1-ol,
2-amino-2-methyl-4-{5-[3-(3-acetylphenoxypropynyl]thiophen-2-yl}butan-1-ol, and
2-amino-2-methyl-4-{5-[3-(4-acetylphenoxy)propynyl]thiophen-2-yl}butan-1-ol.
Preferred compounds of formula (I) also include ones comprising a combination of one group selected from each of the groups consisting of (2) and (3); (4) and (5); (6) and (7); (8) to (10); (11) and (12); (13) to (17); (18) to (29); (30) to (40); (41) and (42).
(45) The present invention includes an optically active amino alcohol derivative of formula (La) or (Lb): 
wherein
R1 and R2 are the same or different and each represents a hydrogen atom or an amino protecting group;
R3a represents a hydrogen atom or a hydroxy protecting group or when R1 is a hydrogen atom, R2 and R3a taken together form a group of formula xe2x80x94(Cxe2x95x90O)xe2x80x94;
R4a represents a C1-C20 alkyl group, a C2-C10 alkyl group interrupted with a heteroatom(s), a C1-C20 alkyl group substituted with an aryl group(s) or a heteroaryl group(s), a C2-C20 a ynyl group, a C3-C20 alkyl group interrupted with a heteroatom(s), a C2-C20 alkynyl group substituted with an aryl group(s) or a heteroaryl group(s), a C2-C20 alkenyl group, a C3-C20 alkenyl group interrupted with a heteroatom(s), a C2-C20 alkenyl group substituted with an aryl group(s) or a heteroaryl group(s), a C2-C20 alkyl group which is substituted with an aryl group(s) or a heteroaryl group(s) and interrupted with a heteroatom(s), or a cycloalkyl group;
m represent an integer from 0 to 4;
Ar represents an aryl group, a heteroaryl group, an aryl group substituted with 1 to 5 substituents selected from substituent group a, a heteroaryl group substituted with 1 to 5 substituents selected from substituent group a, with the proviso that when Ar is an aryl group, R1 is not a hydrogen atom and R2 and/or R3 do not represent a hydrogen atom;
substituent group a represents a halogen atom, a lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group, a lower alkylthio group, a carboxyl group, a lower alkoxycarbonyl group, a hydroxyl group, a lower aliphatic acyl group, an amino group, a lower mono-alkylamino group, a lower di-alkylamino group, a lower aliphatic acylamino group, a cyano group, and a nitro group.
Preferred compounds of formula (La) or (Lb) include the following compounds:
(46) a compound according to (45) wherein said compound has formula (La);
(47) a compound according to (45) or (46) wherein R1 is a hydrogen atom;
(48) a compound according to any one of (45) to (47) wherein R2 and R3a taken together form a group of formula xe2x80x94(Cxe2x95x90O)xe2x80x94;
(49) a compound according to any one of (45) to (47) wherein R3a is a hydrogen atom;
(50) a compound according to any one of (45) to (49) wherein R4a is a C1-C10 alkyl group, a C2-C10 alkyl group interrupted with a heteroatom(s), a C1-C10 alkyl group substituted with an aryl group(s) or a heteroaryl group(s), a C2-C10 alkynyl group, a C3-C10 alkynyl group interrupted with a heteroatom(s), a C2-C10 alkynyl group substituted with an aryl group(s) or a heteroaryl group(s), a C2-C10 alkenyl group, a C3-C10 alkenyl group interrupted with a heteroatom(s), a C2-C10 alkenyl group substituted with an aryl group(s) or a heteroaryl group(s), a C2-C10 alkyl group which is substituted with an aryl group(s) or a heteroaryl group(s) and interrupted with a heteroatom(s), or a C5-C10 cycloalkyl group;
(51) a compound according to any one of (45) to (49) wherein R4a is a C1-C10 alkyl group, a C2-C10 alkyl group interrupted with a heteroatom(s), a C1-C10 alkyl group substituted with an aryl group(s) or a heteroaryl group(s), a C2-C10 alkynyl group, a C2-C10 alkenyl group, or a C5-C10 cycloalkyl group;
(52) a compound according to any one of (45) to (49) wherein R4a is a C1-C10 alkyl group;
(53) a compound according to any one of (45) to (49) wherein R4a is a C1-C6 alkyl group;
(54) a compound according to any one of (45) to (49) wherein R4a is a methyl group or an ethyl group;
(55) a compound according to any one of (45) to (54) wherein Ar is a phenyl, furyl, thienyl or benzothienyl group, said groups optionally being substituted with 1 to 4 substituents selected from substituent group a;
(56) a compound according to any one of (45) to (54) wherein Ar is a thienyl group or a thienyl group substituted with 1 to 4 substituents selected from substituent group a;
(57) a compound according to any one of (45) to (54) wherein Ar is a benzothienyl group or a benzothienyl group substituted with 1 to 4 substituents selected from substituent group a;
(58) a compound according to (45) to (57) wherein m is 0;
(59) a compound according to any one of (45) to (57) wherein substituent group a is a halogen atom, a hydroxyl group, a lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group, a carboxyl group, a lower aliphatic acyl group, a lower aliphatic acylamino group, an amino group, a cyano group, or a nitro group;
(60) The present invention relates to a process for the preparation of a compound of a formula (XLIVa) or (XLIVb) 
[wherein:
R1 and R2 are the same or different and each represents a hydrogen atom or an amino protecting group;
R4a represents a C1-C20 alkyl group, a C2-C20 alkyl group interrupted with a heteroatom(s), a C1-C20 alkyl group substituted with an aryl group(s) or a heteroaryl group(s), a C2-C20 alkynyl group, a C3-C20 alkynyl group interrupted with a heteroatom(s), a C2-C20 alkynyl group substituted with an aryl group(s) or a heteroaryl group(s), a C2-C20 alkenyl group, a C3-C20 alkenyl group interrupted with a heteroatom(s), a C2-C20 alkenyl group substituted with an aryl group(s) or a heteroryl group(s), a C2-C20 alkyl group which is substituted with an aryl group(s) or a heteroaryl group(s) and interrupted with a heteroatom(s), or a cycloalkyl group; and
R11 has the same meaning as that indicated above for R4a.].
The process comprises a selective acylation reaction of one hydroxyl group of a 2-substituted 2-amino-1,3-propanediol derivative of formula (XLII) 
[wherein R1, R2 and R4a are defined in above.]
with a carboxylic acid ester derivative of formula (XLIII)
R11COOCHxe2x95x90CH2xe2x80x83xe2x80x83(XLIII)
[wherein R11 is defined in above.]
in the presence of a lipase to afford a 2-substituted 2-amino-1,3-propanediol mono-ester derivative of formula (XLIVa) or (XLIVb).
(61) a process for preparation according to (60) wherein one of R1 and R2 is a hydrogen atom and the other one is an amino protecting group;
(62) a process for preparation according to (60) or (61) wherein R4a is a C1-C10 alkyl group, a C2-C10 alkyl group interrupted with a heteroatom(s), a C1-C10 alkyl group substituted with an aryl group(s) or a heteroaryl group(s), a C2-C10 alkynyl group, a C3-C10 alkynyl group interrupted with a heteroatom(s), a C2-C10 alkynyl group substituted with an aryl group(s) or a heteroaryl group(s), a C2-C10 alkenyl group, a C3-C10 alkenyl group interrupted with a heteroatom(s), a C2-C10 alkenyl group substituted with an aryl group(s) or a heteroaryl, group(s), a C2-C10 alkyl group which is substituted with an aryl group(s) or a heteroaryl group(s) and interrupted with a heteroatom(s), or a C5-C10 cycloalkyl group;
(63) a process for preparation according to (60) or (61) wherein R4a is a C1-C10 alkyl group, a C2-C10 alkyl group interrupted with a heteroatom(s), a C1-C10 alkyl group substituted with an aryl group(s) or a heteroaryl group(s), a C2-C10 alkynyl group, a C2-C10 alkenyl group, or a C5-C10 cycloalkyl group;
(64) a process for preparation according to (60) or (63) wherein R11 is a C1-C20 alkyl group, or a C1-C2 alkyl group substituted with an aryl group(s) or a heteroaryl group(s).
In the above formulae, an xe2x80x9caryl groupxe2x80x9d and an xe2x80x9caryl moietyxe2x80x9d of an aryl group substituted with 1 to 3 substituents selected from substituent group a; an aryl group substituted with 1 to 3 substituents selected from substituent groups a and b; and an aryl group substituted with 1 to 5 substituents selected from substituent group a in the definition of X, R5, Ar and substituent group b each are, for example, an aromatic hydrocarbon having 6 to 10 carbons such as phenyl, indenyl and naphthyl; preferably a phenyl or naphthyl group and most preferably a phenyl group.
In the above formulae, an xe2x80x9calkylene groupxe2x80x9d and an xe2x80x9calkylene moietyxe2x80x9d of a C1-C10 alkylene group substituted with 1 to 3 substituents selected from substituent group a and b in the definition of Y each are a straight or branched chain alkylene having 1 to 10 carbons such as methylene, methylmethylene, ethylene, propylene, trimethylene, 1-methylethylene, tetramethylene, 1-methyltrimethylene, 2-methyltrimethylene, 3-methyltrimethylene, 1-methylpropylene, 1,1-dimethylethylene, pentamethylene, 1-methyltetramethylene, 2-methyltetramethylene, 3-methyltetramethylene, 4-methyltetramethylene, 1,1-methyltrimethylene, 2,2-dimethyltrimethylene, 3,3-dimethyltrimethylene, hexamethylene, 1-methylpentamethylene, 2-methylpentamethylene, 3-methylpentamethylene, 4-methylpentanethylene, 5-methylpentamethylene, 1,1-dimethyltetraethylene, 2,2-dimethyltetramethylene, 3,3-dimethyltetamethylene, 4,4-dimethyltetramethylene, heptamethylene, 1-methylhexamethylene, 2-methylhexamethylene, 5-methylhexamethylene, 3-ethylpentamethylene, octamethylene, 2-methylheptamethylene, 5-methylheptamethylene, 2-ethylhexamethylene, 2-ethyl-3-methylpentamethylene, 3-ethyl-2-methylpentamethylene, nonamethylene, 2-methyloctamethylene, 7-methyloctamethylene, 4-ethylheptamethylene, 3-ethyl-2-methylhexamethylene, 2-ethyl-1-methylhexamethylene, decamethylene group; preferably a C1-C6 alkylene; more preferably a C1-C5 alkylene; still more preferably an ethylene, trimethylene or tetramethylene group; and most preferably an ethylene or trimethylene group.
In the above formulae, a xe2x80x9cC1-C10 alkylene group which has an oxygen atom or a sulfur atom in said carbon chain or at the end of said carbon chainxe2x80x9d and a xe2x80x9cC1-C10 alkylene moiety which has an oxygen atom or a sulfur atom in said carbon chain or at the end of said carbon chainxe2x80x9d of a C1-C10 alkylene group which is substituted with 1 to 3 substituents selected from substituent groups a and b and has an oxygen atom or a sulfur atom in said carbon chain or at the end of said carbon chain in the definition of Y is a C1-C10 alkylene group indicated above which has an oxygen atom or a sulfur atom in said carbon chain or at the end of said carbon chain, for example, a group of formula xe2x80x94Oxe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94(CH2)2xe2x80x94, xe2x80x94Oxe2x80x94(CH2)3xe2x80x94, xe2x80x94Oxe2x80x94(CH2)4xe2x80x94, xe2x80x94Oxe2x80x94(CH2)5xe2x80x94, xe2x80x94Oxe2x80x94(CH2)6xe2x80x94, xe2x80x94Oxe2x80x94(CH2)7xe2x80x94, xe2x80x94Oxe2x80x94(CH2)8xe2x80x94, xe2x80x94Oxe2x80x94(CH2)9xe2x80x94, xe2x80x94Oxe2x80x94(CH2)10xe2x80x94, xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94Oxe2x80x94(CH2)2xe2x80x94, xe2x80x94CH2xe2x80x94Oxe2x80x94(CH2)3xe2x80x94, xe2x80x94CH2xe2x80x94Oxe2x80x94(CH2)4xe2x80x94, xe2x80x94(CH2)2xe2x80x94Oxe2x80x94CH2xe2x80x94, xe2x80x94(CH2)2xe2x80x94Oxe2x80x94(CH2)2xe2x80x94, xe2x80x94(CH2)2xe2x80x94Oxe2x80x94(CH2)3xe2x80x94, xe2x80x94(CH2)2xe2x80x94Oxe2x80x94(CH2)4xe2x80x94, xe2x80x94(CH2)3xe2x80x94Oxe2x80x94CH2xe2x80x94, xe2x80x94(CH2)3xe2x80x94Oxe2x80x94(CH2)2xe2x80x94, xe2x80x94(CH2)3xe2x80x94Oxe2x80x94(CH2)3xe2x80x94, xe2x80x94(CH2)4xe2x80x94Oxe2x80x94CH2xe2x80x94, xe2x80x94(CH2)4xe2x80x94Oxe2x80x94(CH2)2xe2x80x94, xe2x80x94(CH2)5xe2x80x94Oxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94(CH2)2xe2x80x94Oxe2x80x94, xe2x80x94(CH2)3xe2x80x94Oxe2x80x94, xe2x80x94(CH2)4xe2x80x94Oxe2x80x94, xe2x80x94(CH2)5xe2x80x94Oxe2x80x94, xe2x80x94(CH2)6xe2x80x94Oxe2x80x94, xe2x80x94(CH2)7xe2x80x94Oxe2x80x94, xe2x80x94(CH2)8xe2x80x94Oxe2x80x94, xe2x80x94(CH2)9xe2x80x94Oxe2x80x94, xe2x80x94(CH2)10xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94CH2xe2x80x94, xe2x80x94Sxe2x80x94(CH2)2xe2x80x94, xe2x80x94Sxe2x80x94(CH2)3xe2x80x94, xe2x80x94Sxe2x80x94(CH2)4xe2x80x94, xe2x80x94Sxe2x80x94(CH2)5xe2x80x94, xe2x80x94Sxe2x80x94(CH2)6xe2x80x94, xe2x80x94Sxe2x80x94(CH2)7xe2x80x94, xe2x80x94Sxe2x80x94(CH2)8xe2x80x94, xe2x80x94Sxe2x80x94(CH2)9xe2x80x94, xe2x80x94Sxe2x80x94(CH2)10xe2x80x94, xe2x80x94CH2xe2x80x94Sxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94Sxe2x80x94(CH2)2xe2x80x94, xe2x80x94CH2xe2x80x94Sxe2x80x94(CH2)3xe2x80x94, xe2x80x94CH2xe2x80x94Sxe2x80x94(CH2)4xe2x80x94, xe2x80x94(CH2)2Sxe2x80x94CH2xe2x80x94, xe2x80x94(CH2)2xe2x80x94Sxe2x80x94(CH2)2xe2x80x94, xe2x80x94(CH2)2xe2x80x94Sxe2x80x94(CH2)3xe2x80x94, xe2x80x94(CH2)2xe2x80x94Sxe2x80x94(CH2)4xe2x80x94, xe2x80x94(CH2)3xe2x80x94Sxe2x80x94CH2xe2x80x94, xe2x80x94(CH2)3xe2x80x94Sxe2x80x94(CH2)2xe2x80x94, xe2x80x94(CH2)3xe2x80x94Sxe2x80x94(CH2)3xe2x80x94, xe2x80x94(CH2)4xe2x80x94Sxe2x80x94CH2xe2x80x94, xe2x80x94(CH2)4xe2x80x94Sxe2x80x94(CH2)2xe2x80x94, xe2x80x94(CH2)5xe2x80x94Sxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94Sxe2x80x94(CH2)2xe2x80x94Sxe2x80x94, xe2x80x94(CH2)3xe2x80x94Sxe2x80x94, xe2x80x94(CH2)4xe2x80x94Sxe2x80x94, xe2x80x94(CH2)5xe2x80x94Sxe2x80x94, xe2x80x94(CH2)6xe2x80x94Sxe2x80x94, xe2x80x94(CH2)7xe2x80x94Sxe2x80x94, xe2x80x94(CH2)8xe2x80x94Sxe2x80x94, xe2x80x94(CH2)9xe2x80x94Sxe2x80x94, xe2x80x94(CH2)10xe2x80x94Sxe2x80x94; preferably a C1-C6 alkylene group which has an oxygen atom in said carbon chain or at the end of carbon chain; more preferably xe2x80x94Oxe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94(CH2)2xe2x80x94, xe2x80x94Oxe2x80x94(CH2)3xe2x80x94, xe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94(CH2)2xe2x80x94Oxe2x80x94, or xe2x80x94(CH2)3xe2x80x94Oxe2x80x94; and most preferably xe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94(CH2)2xe2x80x94, or xe2x80x94(CH2)2xe2x80x94Oxe2x80x94.
In the above formulae the xe2x80x9ccycloalkyl groupsxe2x80x9d in substituent groups b and the xe2x80x9ccycloalkyl moietiesxe2x80x9d of the cycloalkyl group substituted with 1 to 3 substituents selected from substituent group a and the cycloalkyl group substituted with 1 to 3 substituents selected from substituent groups a and b in the definitions of R4a, R5 and R11, each comprise a saturated carbon ring having 3 to 10 carbons, which is optionally fused with a cyclic group(s) such as a benzene ring, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, adamantyl and indanyl. A preferred cycloalkyl group in the definition of R5 and substituent group b is a C5-C6 cycloalkyl group and the most preferred one is a cyclohexyl group. On the other hand a preferred cycloalkyl group in the definition of R4a and R11 is a C5-C10 cycloalkyl group.
In the above formulae the xe2x80x9cheteroaryl groupxe2x80x9d and the xe2x80x9cheteroaryl moietyxe2x80x9d of the heteroaryl group substituted with 1 to 5 substituents selected from substituent group a in the definition of Ar each comprise a 5- to 7-membered heterocyclic group having 1 to 3 of a sulfur atom(s), an oxygen atom(s) and/or a nitrogen atom(s), for example, furyl, thienyl, pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl.
In addition, the heteroaryl group indicated above optionally may be fused with a cyclic group. Examples of such a group include, for example, benzothienyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathiinyl, indolizinyl, isoindolyl, indolyl, indazolyl purinyl, quinolizinyl isoquinolyl, quinolyl, phthalazinyl, naphthylizinyl, quinoxalinyl, quinazolinyl, carbazolyl, carbolinyl, acridinyl and isoindolinyl. Preferred heteroaryl groups are a furyl, thienyl or benzothienyl group and the most preferred heteroaryl group is a thienyl or a benzothienyl group.
In the above formulae the xe2x80x9cheterocyclic groupsxe2x80x9d in the definition of R5 and substituent group b and the xe2x80x9cheterocyclic moietyxe2x80x9d of the heterocyclic group substituted with 1 to 3 substituents selected from substituent group a and the heterocyclic group substituted with 1 to 3 substituents selected from substituent groups a and b each represent a 5- to 7 membered heterocyclic group having 1 to 3 of a sulfur atom(s), an oxygen atom and/or a nitrogen atom, and examples of such heterocyclic groups include the heteroaryl groups indicated above, and heterocyclic compounds corresponding to partially or completely hydrogenated heteroaryl groups indicated above such as tetrahydropyranyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, pyrrolyl imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl and pyrazolidinyl. Preferred heterocyclic groups are 5- or 6-membered heteroaryl groups and the most preferred heterocyclic group is a morpholinyl thiomorpholinyl or piperidinyl group.
In the above formulae the xe2x80x9chalogen atomxe2x80x9d in the definition of substituent group a is a fluorine, chlorine, bromine or iodine atom; preferably a fluorine atom or chlorine atom and most preferably a fluorine atom.
In the above formulae the xe2x80x9clower alkyl groupsxe2x80x9d in the definition of R4 and substituent group a each represent, for example, a straight or branched chain alkyl group having 1 to 6 carbons such as a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 1-ethylbutyl or 2-ethylbutyl group; preferably a C1-C4 alkyl group; more preferably a C1-C2 alkyl group and most preferably a methyl group.
In the above formulae the xe2x80x9chalogenated lower alkyl groupxe2x80x9d in the definition of substituent group a represents the lower alkyl group, which is described hereinbefore which is substituted with a halogen atom(s), for example, a halogenated C1-C6 alkyl group such as a trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, dibromomethyl, fluoromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 2-bromoethyl, 2-chloroethyl, 2-fluoroethyl, 2-iodoethyl, 3-chloropropyl, 4-fluorobutyl, 6-iodohexyl or 2,2-dibromoethyl group; preferably a halogenated C1-C4 alkyl group; more preferably a halogenated C1-C2 alkyl group; and most preferably a trifluoromethyl group.
In the above formulae the xe2x80x9clower alkoxy groupxe2x80x9d in the definition of substituent group a represents an oxygen atom which is attached to the lower alkyl group described hereinbefore, for example, a straight or branched chain alkoxy group having 1 to 6 carbons such as a methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentoxy, isopentoxy, 2-methylbutoxy, 1-ethylpropoxy, 2-ethylpropoxy, neopentoxy, hexyloxy, 4-methylpentoxy, 3-methylpentoxy, 2-methylpentoxy, 3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy or 2,3-dimethylbutoxy group; preferably a C1-C4 alkoxy group; more preferably a C1-C2 alkoxy group; and most preferably a methoxy group.
In the above formulae the xe2x80x9clower alkylthio groupxe2x80x9d in the definition of substituent group a represents a sulfur atom which is attached to a lower alkyl group described hereinbefore, for example, an alkylthio group having 1 to 6 carbons such as a methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, s-butylthio, t-butylthio, pentylthio, isopentylthio, 2-methylbutylthio, neopentylthio, hexylthio, s-methylpentylthio, 3-methylpentylthio, 2-methylpentylthio, 3,3-dimethylbutylthio, 2,2-dimethylbutyithio, 1,1-dimethylbutylthio, 1,2-dimethylbutylthio, 1,3-dimethylbutylthio or 2,3-dimethylbutylthio group; preferably a C1-C4 alkylthio group; more preferably a C1-C2 alkylthio group; and most preferably a methylthio group.
In the above formulae the xe2x80x9clower alkoxycarbonyl groupxe2x80x9d in the definition of substituent group a represents a carbonyl group which is attached to the lower alkoxy group described hereinbefore, for example, a straight or branched chain alkoxycarbonyl group having 1 to 6 carbons such as a methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, s-butoxycarbonyl, t-butoxycarbonyl, pentoxycarbonyl, isopentoxycarbonyl, 2-methylbutoxycarbonyl, neopentoxycarbonyl, hexyloxycarbonyl, 4-methylpentoxycarbonyl, 3-methylpentoxycarbonyl, 2-methylpentoxycarbonyl, 3,3-dimethylbutoxycarbonyl, 2,2-dimethylbutoxycarbonyl, 1,1-dimethylbutoxycarbonyl, 1,2-dimethylbutoxycarbonyl, 1,3-dimethylbutoxycarbonyl or 2,3-dimethylbutoxycarbonyl group; preferably a C1-C4 alkoxycarbonyl group; more preferably a C1-C2 alkoxycarbonyl group; and most preferably a methoxycarbonyl group.
In the above formulae the xe2x80x9clower aliphatic acyl groupxe2x80x9d in the definition of substituent group a represents a carbonyl group which is attached to a hydrogen atom or a saturated or unsaturated chain hydrocarbon, for example, a straight or branched chain lower aliphatic acyl group having 1 to 7 carbons such as a formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovalaryl, pivaloyl, hexanoyl, acryloyl, methacryloyl or crotonoyl group; preferably a C1-C4 lower aliphatic acyl group; more preferably an acetyl or propionyl group; and most preferably an acetyl group.
In the above formulae the xe2x80x9cmono lower alkylamino groupxe2x80x9d in the definition of substituent group a represents an amino group which is attached to one alkyl group described hereinbefore, for example, a mono C1-C6 alkylamino group such as a methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, s-butylamino, t-butylamino, pentylamino, isopentylamino, 2-methylbutylamino, neopentylamino, 1-ethylpropylamino, hexylamino, isohexylamino, 4-methylpentylamino, 3-methylpentylamino, 2-methylpentylamino, 1-methylpentylamino, 3,3-dimethylbutylamino, 2,2-dimethylbutylamino, 1,1-dimethylbutylamino, 1,2-dimethylbutylamino, 1,3-dimethylbutylamino, 2,3-dimethylbutylamino or 2-ethylbutylamino group; preferably a C1-C4 alkylamino group; more preferably a C1-C2 alkyl amino group; and most preferably a methylamino group.
In the above formulae the xe2x80x9cdi lower alkylamino groupxe2x80x9d in the definition of substituent group a represents an amino group which is attached to two alkyl groups described hereinbefore, for example, a di C1-C6 alkylamino group such as a dimethylamino, diethylamino, N-ethyl-N-methylamino, dipropylamino, dibutylamino, dipentylamino or dihexylamino group; preferably a di C1-C4 alkylamino group; more preferably a di C1-C2 alkyl amino group; and most preferably a dimethylamino group.
In the above formulae the xe2x80x9clower aliphatic acylamino groupxe2x80x9d in the definition of substituent group a represents, for example, a straight or branched chain aliphatic acylamino group having 1 to 7 carbons such as a formylamino, acetylamino, propionylamino, butyrylamino, isobutyrylamino, valerylamino, isovalerylamino, pivaloylamino, hexanoylamino, acryloylamio, methacryloylamino or crotonoylamino group; preferably an acetylamino or propionylamino group; and most preferably an acetylamino group.
In the above formulae the xe2x80x9camino protecting groupsxe2x80x9d in the definition of R1 and R2 each represent an amino protecting group known to those skilled in organic synthesis, for example:
the lower alkyl group described hereinbefore; an aliphatic acyl group, for example, the lower aliphatic acyl group described hereinbefore, a halogenated lower aliphatic acyl group such as chloroacetyl, dichloroacetyl, trichloroacetyl or trifluoroacetyl or a lower aliphatic acyl group substituted with a lower alkoxy group such as methoxyacetyl; an aromatic acyl group, for example, an aromatic acyl group such as bennoy, 1-indancarbonyl, 2-indancarbonyl or 1- or 2-naphthoyl, or an aromatic acyl group substituted with 1 to 3 substituents selected from substituent group a such as 4-chlorobenzoyl, 4-fluorobenzoyl, 2,4,6-trimethylbenzoyl, 4-toluoyl, 4-anisoyl, 4-nitrobenzoyl, 2-nitrobenzoyl, 2-(methoxycarbonyl)benzoyl or 4-phenylbenzoyl; an alkoxylcarbonyl group, for example, the lower alkoxylcarbonyl described hereinbefore or a lower alkoxycarbonyl group substituted with a halogen atom(s) or a tri lower alkylsilyl group(s) such as 2,2,2-trichloroethoxycarbonyl or 2-trimethylsilylethoxycarbonyl; an alkenyloxycarbonyl group such as vinyloxycarbonyl or allyloxycarbonyl; an aralkyloxycarbonyl group, for example, an aralkyloxycarbonyl group such as a benzyloxycarbonyl group or an aralkyloxycarbonyl group substituted with 1 to 3 substituents selected from substituent group a such as 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxybonyl, 2-nitrobenzyloxycarbonyl or 4-nitrobenzyloxycarbonyl; a silyl group, for example, a lower alkylsilyl group such as trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, methyldiisopropylsilyl, methyl-di-t-butylsilyl or triisopropylsilyl, a silyl group tri substituted with an aryl group(s) or with an aryl(s) and a lower alkyl group(s) such as diphenylmethylsilyl or diphenylbutylsilyl, diphenylisopropylsilyl phenyldiisopropylsilyl; an aralkyl group, for example a lower alkyl group substituted with 1 to 3 aryl groups such as benzyl, phenethyl, 3-phenylpropyl, xcex1-naphthylmethyl, xcex2-naphthylmethyl, diphenylmethyl, triphenylmethyl, xcex1-naphthyldiphenylmethyl or 9-anthrylmethyl or a lower alkyl group substituted with 1 to 3 substituted aryl groups wherein said aryl group is substituted with lower alkyl, lower alkoxy, nitro, halo or cyano, such as 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxy-phenyldiphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-cyanobenzyl, 4-cyanobenzyldiphenylmethyl, bis(2-nitrophenyl)methyl or piperonyl; and a substituted methylene group which forms a Schiff base such as N,N-dimethylaminomethylene, benzylidene, 4-methoxybenzylidene, 4-nitrobenzylidene, salicylidene, 5-chlorosalicylidene, diphenylmethylene or (5-chloro-2-hydroxyphenyl)phenylmethylene; preferably a lower alkoxycarbonyl group, an aralkyloxycarbonyl group or an aralkyloxycarbonyl group substituted with 1 to 3 substituents selected from substituent group a.
The xe2x80x9chydroxy protecting groupxe2x80x9d in the definition R3 and R3a represents a general protecting group which can be deprotected by a chemical process such as hydrogenolysis, hydrolysis, electrolysis, photolysis and a protecting group which can be deprotected by a biological process such as hydrolysis in vivo.
Examples of general protecting groups includes the lower alkyl groups described hereinbefore; the aliphatic acyl groups described hereinbefore; the aromatic acyl groups described hereinbefore; a tetrahydropyranyl or tetrahydrothiopyranyl group such as tetrahydropyran-2-yl, 3-bromotetrahydropyran-2-yl or 4-methoxy tetrahydropyran-4-yl, tetrahydrothiopyran-2-yl or 4-methoxytetrahydrothiopyran-4-yl; a tetrahydrofuranyl or tetrahydrothiofuranyl group such as tetrahydrofuran-2-yl or tetrahydrothiofuran-2-yl; the silyl groups described hereinbefore; an alkoxymethyl group, for example, a lower alkoxylated lower alkoxymethyl group such as methoxymethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl or t-butoxymethyl; a lower alkoxylated alkoxymethyl group such as 2-methoxyethoxymethyl or a halogenated lower alkoxymethyl group such as 2,2,2-trichloroethoxymethyl or bis(2-chloroethoxy)methyl; a substituted ethyl group, for example a lower alkoxylated ethyl group such as 1-ethoxyethyl or 1-(isopropoxy)ethyl or a halogenated ethyl group such as 2,2,2-trichloroethyl; the aralkyl groups described hereinbefore; the alkoxycarbonyl groups described hereinbefore; and the alkenyloxycarbonyl group described hereinbefore; the aralkyloxycarbonyl group described hereinbefore.
On the other hand examples of a protecting group which can be deprotected by a biological process such as hydrolysis in vivo, include an acyloxyalkyl group such as ethylcarbonyloxymethyl, pivaloyloxymethyl, dimethylaminoacetyloxymethyl or 1-acetoxyethyl; a 1-(alkoxycarbonyloxy)alkyl group such as 1-(methoxycarbonyloxy)ethyl, 1-(ethoxycarbonyloxy)ethyl, ethoxycarbonyloxymethyl, 1-(isopropoxycarbonyloxy)ethyl, 1-(t-butoxycarbonyloxy)ethyl, 1-(ethoxycarbonyloxy)propyl or 1-(cyclohexyloxycarbonyloxy)ethyl; a phthalidyl group; a carbonyloxyalkyl group, for example, an oxodioxolenylmethyl group such as 4-methyloxodioxolenylmethyl or 4-phenyloxodioxolenylmethyl; the aliphatic acyl groups described hereinbefore; the aromatic acyl groups described hereinbefore; a residual group of a half ester of succinic acid; a residual group of an ester of phosphoric acid; a residual group of an ester formation of an amino acid; a carbamoyl group; an alkylidene group such as benzylidene; an alkoxyethylidene group such as methoxyethylidene or ethoxyethylidene; a protecting group of two hydroxyl groups such as oxomethylene or oxoethylene; and a carbonyloxyalkyloxycarbonyl group such as pivaloyloxymethyloxycarbonyl.
Whether a compound of formula (I) has such a group can be determined as follows. The derivative under investigation is intravenously administered to a test animal such as a rat or mouse and the body fluids of the test animal are thereafter studied. If the parent compound of said derivative or a pharmaceutically acceptable salt of the parent compound is detected in said body fluid, said derivative under investigation is judged to have a protecting group which can be deprotected by biological process. Examples of such a hydroxy protecting group are preferably a lower alkyl group, a lower aliphatic acyl group, an aromatic acyl group or an aromatic acyl group substituted with 1 to 3 substituents selected from substituent group a
In the above formulae typical examples of the xe2x80x9ccycloalkyl group substituted with 1 to 3 substituents selected from substituent groups a and bxe2x80x9d in the definition of R5 are, for example, a 2-fluorocyclopropyl, 2-chlorocyclopropyl, 2- or 3-fluorocyclopentyl, 2- or 3-chlorocyclopentyl, 2-, 3- or 4-fluorocyclohexyl, 2-, 3- or 4-chlorocyclohexyl, 2-, 3- or 4-bromocyclohexyl, 2-, 3- or 4-iodocyclohexyl, 2-methylcyclopropyl 2-ethylcyclopropyl, 2- or 3-methylcyclopentyl, 2- or 3-ethyleyelopentyl, 2-, 3- or 4-methylcyclohexyl, 2-, 3- or 4-ethylcyclohexyl, 2-trifluoromethylcyclopropyl, 2- or 3-trifluoromethylcyclobutyl, 2- or 3-trifluoromethylcyclopentyl, 2-, 3- or 4-trifluoromethylcyclohexyl, 2-methoxycyclopropyl, 2- or 3-methoxycyclobutyl, 2- or 3-methoxycyclopentyl, 2-, 3- or 4-methoxycyclohexyl, 2-, 3- or 4-ethoxycyclohexyl, 2-, 3- or 4-propoxycyclohexyl, 2-, 3- or 4-isopropoxycyclohexyl, 2-, 3- or 4-(1-ethylpropoxy)cyclohexyl, 2-, 3- or 4-(2-ethylpropoxycyclohexyl, 2-carboxycyclopropyl, 2- or 3-carboxycyclopentyl, 2-, 3- or 4-carboxycyclohexyl, 2-methoxycarbonylcyclopropyl, 2- or 3-methoxycarbonylcyclopentyl, 2-, 3- or 4-methoxycarbonylcyclohexyl, 2-hydroxycyclopropyl, 2- or 3-hydroxycyclopentyl, 2-, 3- or 4-hydroxycyclohexyl, 2-formylcyclopropyl, 2- or 3-formylcyclopentyl, 2-, 3- or 4-formylcyclohexyl, 2-acetylcyclopropyl, 2- or 3-acetylcyclopentyl, 2-, 3- or 4-acetylcyclohexyl, 2-aminocyclopropyl, 2- or 3-aminocyclopentyl, 2-, 3- or 4-aminocyclohexyl, 2-methylaminocyclopropyl, 2- or 3-methylaminocyclobutyl, 2- or 3-methylaminocyclopentyl, 2-, 3- or 4-methylaminocyclohexyl, 2-dimethylaminocyclopropyl, 2- or 3-dimethylaminocyclobutyl, 2- or 3-dimethylaminocyclopentyl, 2-, 3- or 4-dimethylaminocyclohexyl, 2-cyanocyclopropyl, 2- or 3-cyanocyclopentyl, 2-, 3- or 4-cyanocyclohexyl, 2- or 3-cyclohexylcyclopentyl, 2-, 3- or 4-cyclohexylcyclohexyl, 2-phenylcyclopropyl, 2- or 3-phenylcyclopentyl, 2-, 3- or 4-phenylcyclohexyl, 3,4-difluorocyclohexyl, 3,4-dichlorocyclohexyl, 2,3-dimethoxycyclohexyl, 3,4-dimethoxycyclohexyl, 3,5-methoxycyclohexyl, or 3,4,5-trimethoxycyclohexyl group; preferably a cycloalkyl group substituted with 1 to 3 substituents (said substituent is selected from the group consisting of a halogen atom, a lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group, a lower alkylthio group, and a lower aliphatic acyl group); more preferably a cycloalkyl group substituted with 1 to 3 substituents (said substituent is selected from the group consisting of a halogen atom, a lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group, and a lower aliphatic acyl group); still more preferably a cyclohexyl group substituted with 1 to 3 substituents (said substituent is selected from the group consisting of a halogen atom, a lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group, and a lower aliphatic acyl group); most preferably a cyclohexyl group substituted with 1 to 3 substituents (said substituent is selected from the group consisting of a fluorine atom, a chlorine atom, and methyl, trifluoromethyl, methoxy and acetyl groups).
In the above formulae typical examples of the xe2x80x9caryl group substituted with 1 to 3 substituents selected from substituent groups a and bxe2x80x9d in the definition of R5 are, for example, a 2-, 3- or 4-fluorophenyl, 2-, 3- or 4-chlorophenyl, 2-, 3- or 4-bromophenyl, 2-, 3- or 4-iodophenyl, 2-, 3- or 4-methylphenyl, 2-, 3- or 4-ethylphenyl, 2-, 3- or 4-propylphenyl, 2-, 3- or 4-butylphenyl, 2-, 3- or 4-pentylphenyl, 2-, 3- or 4-trifluoromethylphenyl, 2-, 3- or 4-methoxyphenyl, 2-, 3- or 4-ethoxyphenyl, 2-, 3- or 4-propoxyphenyl, 2-, 3- or 4-isopropoxyphenyl, 2-, 3- or 4-butoxyphenyl, 2-, 3- or 4-(1-ethylpropoxyphenyl, 2-, 3- or 4-(2-ethylpropoxy)phenyl, 2-, 3- or 4-methylthiophenyl, 2-, 3- or 4-ethylthiophenyl, 2-, 3- or 4-carboxyphenyl, 2-, 3- or 4-methoxycarbonylphenyl, 2-, 3- or 4-ethoxycarbonylphenyl, 2-, 3- or 4-hydroxyphenyl, 2-, 3- or 4-formylphenyl, 2-, 3- or 4-acetylphenyl, 2-, 3- or 4-aminophenyl, 2-, 3- or 4-methylaminophenyl, 2-, 3- or 4-dimethylaminophenyl, 2-, 3- or 4-cyanophenyl, 2-, 3- or 4-cyclopentylphenyl, 2-, 3- or 4-cyclohexylphenyl, 2-, 3- or 4-biphenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 3,4-bromophenyl, 2,3-dimethylphenyl, 3,4-dimethylphenyl, 3,5-dimethylphenyl, 2,3-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 3-fluoro-4-methoxyphenyl, 4-methyl-2-methoxyphenyl, 6-fluoro-4-methyl-2-methoxyphenyl, 5-fluoroinden-3-yl, 5-fluoroinden-3-yl, 5-methylinden-3-yl, 5-methoxyinden-3-yl, 5-fluoroinden-2-yl, 5-chloroinden-2-yl, 5-methylinden-2-yl, 5-methoxyinden-2-yl, 5-hydroxyinden-3-yl, 5-nitroinden-3-yl, 5-cyclohexylinden-3-yl, 5-phenylinden-3-yl, 5-phenoxyinden-3-yl, 5-benzyloxyinden-3-yl, 5-phenylthioinden-3-yl, 5-hydroxyinden-2-yl, 5-nitroinden-2-yl, 5-cyclohexylinden-2-yl, 5-phenylinden-2-yl, 5-fluoronaphthalen-2-yl, 5-methylnaphthalen-2-yl, 5-methoxynaphthalen-2-yl, 5-fluoronaphthalen-1-yl, 5-methylnaphthalen-1-yl, 5-methoxynaphthalen-1-yl, 5-hydroxyraphthalen-2-yl, 5-nitronaphthalen-2-yl, 5-cyclohexylnaphthalen-2-yl, 5-phenylnaphthalen-2-yl, 5-phenoxynaphthalen-2-yl, 5-benzyloxynaphthalen-2-yl, 5-phenylthionaphthalen-2-yl, 5-hydroxynaphthalen-1-yl, 5-nitronaphthalen-1-yl, 5-cyclohexylnaphthalen-1-yl or 5-phenyhlaphthalen-1-yl group; preferably an aryl group substituted with 1 to 3 substituents (said substituent is selected from the group consisting of a halogen atom, a lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group, a lower alkylthio group and a lower aliphatic acyl group); more preferably an aryl group substituted with 1 to 3 substituents (said substituent is selected from the group consisting of a halogen atom, a lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group, and a lower aliphatic acyl group); more preferably a phenyl group substituted with 1 to 3 substituents (said substituent is selected from the group consisting of a halogen atom, a lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group, and a lower aliphatic acyl group); still more preferably a phenyl group substituted with 1 to 3 substituents (said substituent is selected from the group consisting of a fluorine atom, a chlorine atom and methyl, trifluoromethyl, methoxy and acetyl groups); and most preferably a 3-fluorophenyl, 4-fluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 3-methylphenyl, 4-methylphenyl, 3,4-dimethylphenyl, 3,5-dimethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3,4-ditrifluoromethylphenyl, 3,5-ditrifluoromethylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 3-acetylphenyl, or 4-acetylphenyl group.
In the above formulae typical examples of the xe2x80x9cheterocyclic group substituted with 1 to 3 substituents selected from substituent groups a and bxe2x80x9d in the definition of R5 are, for example, a 3-, 4- or 5-methylfuran-2-yl, 2-, 4- or 5-methylfuran-3-yl, 3-, 4- or 5-fluorothiophen-2-yl, 2-, 4- or 5-fluorofuran-3-yl, 3-, 4- or 5-bromothiophen-2-yl, 2-, 4- or 5-bromofuran-3-yl, 3-, 4- or 5-methylthiophen-2-yl, 2-, 4- or 5-methylthiophen-3-yl, 3-, 4- or 5-ethylthiophen-2-yl, 2-, 4- or 5-ethylthiophen-3-yl, 3-, 4- or 5-methoxythiophen-2-yl, 2-, 4- or 5-methoxythiophen-3-yl, 3- or 4-methylthiazol-5-yl, 3-, 4- or 5-fluorobenzothiophen-2-yl, 3-, 4- or 5-bromobenzothiophen-2-yl, 3-, 4- or 5-methylbenzothiophen-2-yl, 3-, 4- or 5-methoxybenzothiophen-2-yl, 2-, 4- or 5-fluorobenzothiophen-3-yl, 2-, 4- or 5-bromobenzothiophen-3-yl, 2-, 4- or 5-methylbenzothiophen-3-yl, 2-, 4- or 5-methoxybenzothiophen-3-yl, 4-, 5-, 6- or 7-methylbenzothiophen-2-yl, 3-, 4- or 5-hydroxyfuran-2-yl, 2-, 4- or 5-hydroxyfuran-3-yl, 3-, 4- or 5-hydroxythiophen-2-yl, 3-, 4- or 5-nitrothiophen-2-yl, 3-, 4- or 5-phenylthiophen-2-yl, 2-, 4- or 5-hydroxythiophen-3-yl, 2-, 4- or 5-cyanothiophen-3-yl, 1-, 2- or 3-hydroxypyridinyl, 1-, 2- or 3-cyanopyridinyl or 1-, 2- or 3-phenylpyridin-4-yl group; and preferably a 3-, 4- or 5-fluorothiophen-2-yl or 3-, 4-, or 5-fluorofuran-3-yl group.
In the above formulae examples of the xe2x80x9cC1-C20 alkyl groupsxe2x80x9d in the definition of R4a and R11 are, for example, a straight or branched chain alkyl group having 1 to 20 carbons such as the lower alkyl groups described hereinbefore, heptyl, 1-methylhexyl, 2-methylbexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 1-propylbutyl, 4,4-dimethylpentyl, octyl, 1-methylheptyl, 2-methylheptyl, 3-methylheptyl, 4-methylheptyl, 5-methylheptyl, 6-methylheptyl, 1-propylpentyl, 2-ethylhexyl, 5,5-dimethylhexyl, nonyl, 3-methyloctyl, 4-methyloctyl, 5-methyloctyl, 6-methyloctyl, 1-propylhexyl, 2-ethylheptyl, 6,6-dimethylheptyl, decyl, 1-methylnonyl, 3-methylnonyl, 8-methylnonyl, 3-ethyloctyl, 3,7-dimethyloctyl, 7,7-dimethyloctyl, undecyl, 4,8-dimethylnonyl, dodecyl, tridecyl, tetradecyl, pentadecyl, 3,7,11-trimethyldodecyl, hexadecyl, 4,8,12-trimethyltridecyl, 1-methylpentadecyl, 14-methylpentadecyl, 13,13-dimethyltetradecyl, heptadecyl, 15-methylhexadecyl, octadecyl, 1-methylheptadecyl, nonadecyl, icosyl and 3,7,11,15-tetramethylhexadecyl group; preferably a C1-C10 alkyl group; more preferably a C1-C6 alkyl group; and most preferably a methyl or ethyl group.
In the above formulae the xe2x80x9cC2-C20 alkyl group interrupted with a hetero atom(s)xe2x80x9d in the definition of R4a and R11 represents the C2-C20 alkyl groups which are described hereinbefore and which are interrupted with 1 or 2 of the same or different heteroatoms such as a sulfur atom, an oxygen atom or a nitrogen atom. Examples of such group include an alkyl group, which has 2 to 20 carbons and is interrupted with one or two sulfur atoms, such as methylthiomethyl, 1-methylthioethyl, 2-methylthioethyl, ethylthiomethyl, 1-methylthiopropyl, 2-methylthiopropyl, 3-methylthiopropyl, 2-ethylthioethyl, 2-methyl-2-methylthioethyl, 1-methylthiobutyl, 2-methylthiobutyl, 3-methylthiobutyl, 2-ethylthiopropyl, 3-methyl-3-methylthiopropyl, 4-methylthiopentyl, 3-methylthiopentyl, 2-methylthiopentyl, 1-methylthiopentyl, 3,3-dimethylthiobutyl, 2,2-dimethylthiobutyl, 1,1-dimethylthiobutyl, 1-methyl-2-methylthiobutyl, 1,3-methylthiobutyl, 2,3-dimethylthiobutyl, 2-ethylthiobutyl, 1-methylthiohexyl, 2-methylthiohexyl, 3-methylthiohexyl, 4-methylthiohexyl, 5-methylthiohexyl, 1-propylthiobutyl, 4-methyl-4-methylthiopentyl, 1-methylthioheptyl, 2-methylthioheptyl, 3-methylthioheptyl, 4-methylthioheptyl, 5-methylthioheptyl, 6-methylthioheptyl, 1-propylthiopentyl, 2-ethylthiohexyl, 5-methyl-5-methylthiohexyl, 3-methylthiooctyl, 4-methylthiooctyl, 5-methylthiooctyl, 6-methylthiooctyl, 1-propylthiohexyl, 2-ethylthioheptyl, 6-methyl-methyithioheptyl, 1-methylthiononyl, 3-methylthiononyl, 8-methylthiononyl, 3-ethylthiooctyl, 3-methyl-7-methylthiooctyl, 7,7-dimethylthiooctyl, 4-methyl-8-methylthiononyl, 3,7-dimethyl-11-methylthiododecyl, 4,8-diethyl-2-methylthiotridecyl, 1-methylthiopentadecyl, 14-methylthiopentadecyl, 13-methyl-13-methylthiotetradecyl, 15-methylthiohexadecyl, 1-methylthioheptadecyl, and 3,7,11-trimethyl-15-methylthiohexadecyl; an alkyl group, which has 2 to 20 carbons and is interrupted with one or two oxygen atoms, such as methyloxymethyl, 1-methyloxyethyl, 2-methyloxyethyl, ethyloxymethyl, 1-methyloxypropyl, 2-methyloxypropyl, 3-methyloxypropyl, 2-ethyloxyethyl, 2-methyl-2-methyloxyethyl, 1-methyloxybutyl, 2-methyloxybutyl, 3-methyloxybutyl, 2-ethyloxypropyl, 3-methyl-3-methyloxypropyl, 4-methyloxypentyl, 3-methyloxypentyl, 2-methyloxypentyl, 1-methyloxypentyl, 3,3-dimethyloxybutyl, 2,2-dimethyloxybutyl, 1,1-dimethyloxybutyl, 1-methyl-2-methyloxybutyl, 1,3-dimethyloxybutyl, 2,3-dimethyloxybutyl, 2-ethyloxybutyl, 1-methyloxyhexyl, 2-methyloxyhexyl, 3-methyloxyhexyl, 4-methyloxyhexyl, 5-methyloxyhexyl, 1-propyloxybutyl, 4-methyl-4-methyloxypentyl, 1-methyloxyheptyl, 2-methyloxyheptyl, 3-methyloxyheptyl, 4-methyloxyheptyl, 5-methyloxyheptyl, 6-methyloxyheptyl, 1-propyloxypentyl, 2-ethyloxyhexyl, 5-methyl-5-methyloxyhexyl, 3-methyloxyoctyl, 4-methyloxyoctyl, 5-methyloxyoctyl, 6-methyloxyoctyl, 1-propyloxyhexyl, 2-ethyloxyheptyl, 6-methyl-6-methyloxyheptyl, 1-methyloxynonyl, 3-methyloxynonyl, 8-methyloxynonyl, 3-ethyloxyoctyl, 3-methyl-7-methyloxyoctyl, 7,7-methyloxyoctyl, 4-methyl-8-methyoxynonyl, 3,7-dimethyl-11-methyloxydodecyl, 4,8-dimethyl-12-methyloxytridecyl, 1-methyloxypentadecyl, 14-methyloxypentadecyl, 13-methyl-13-methyloxytetradecyl, 15-methyloxyhexadecyl, 1-methyloxyheptadecyl, and 3,7,11-trimethyl-15-methyloxyhexadecyl; an alkyl group, which has 1 to 20 carbons and is interrupted with one or two nitrogen atoms, such as N-methylaminomethyl, 1-methylamino)ethyl, 2-(N-methylamio)ethyl, N-ethylaminomethyl, 1-(N-methylamino)propyl, 2-(N-methylamino)propyl, 3-(N-methylamino)propyl, 2-(N-ethylamino)ethyl, 2-(N,N-dimethylamino)ethyl, 1-(N-methylamino)butyl, 2-(N-methylamino)butyl, 3-(N-methylamino)butyl, 2-(N-ethylamino)propyl, 3-(N,N-dimethylamino)propyl, 4-(N-methylamino)pentyl, 3-(N-methylamino)pentyl, 2-(N-methylamino)pentyl, 1-(N-methylamino)pentyl, 3-(N,N-dimethylamino)butyl, 2-(N,N-dimethylamino)butyl, 1-(N,N-dimethylamino)butyl, 1-methyl-2-(N-methylamino)butyl, 1,3-di(N-methylamino)butyl, 2,3-di(N-methylamino)butyl, 2-(N-ethylamino)butyl, 1-(N-methylamino)hexyl, 2-(N-methylamino)hexyl, 3-(N-methylamino)hexyl, 4-(N-methylamino)hexyl, 5-(N-methylamino)hexyl, 1-(N-propylamino)butyl, 4-methyl-4-(N-methylamino)pentyl, 1-(N-methylamino)heptyl, 2-(N-methylamino)heptyl, 3-(N-methylamino)heptyl, 4-(N-methylamino)heptyl, 5-(N-methylamino)heptyl, (N-methylamino)heptyl, 1-(N-propylamino)pentyl, 2-(N-ethylamino)hexyl, 5-methyl-5-(N-methylamino)hexyl, 3-(N-methylamino)octyl, 4-(N-methylamino)octyl, 5-(N-methylamino)octyl, 6-(N-methylamino)octyl, 1-(N-propylamino)hexyl, 2-(N-ethylamino)heptyl, 6-methyl(N-methylamio)heptyl, 1-(N-methylamino)nonyl, 3-(N-methylamino)nonyl, 8-(N-methylamino)nonyl, 3-(N-ethylamino)octyl, 3-methyl-7-(N-methylamino)octyl, 7,7-di(N-methylamino)octyl, 4-methyl-8-(N-methylamino)nonyl, 3,7-dimethyl-11-(N-methylamino)dodecyl, 4,8-dimethyl-12-(N-1-(N-methylamino)pentadecyl, 14-(N-methylamino)pentadecyl, 13-methyl-13-(N-methylamino)tetradecyl, 15-(N-methylamino)hexadecyl, 1-(N-methylamino)heptadecyl, and 3,7,11-trimethyl-5-(N-methylamino)hexadecyl; and preferably a C2-C10 alkyl group interrupted with a heteroatom(s).
In the above formulae the xe2x80x9cC1-C20 alkyl group substituted with an aryl group(s) or a heteroaryl group(s)xe2x80x9d in the definition of R4a and R11 represents the C1-C20 alkyl groups described hereinbefore substituted with 1 to 3 of the same or different aryl groups described hereinbefore or the same or different heteroaryl groups described hereinbefore.
In the above formulae the xe2x80x9cC2-C20 alkynyl groupxe2x80x9d in the definition of R4a and R11 comprises, for example, a straight or branched chain alkynyl group having 2 to 20 carbons such as an ethynyl, 2-propynyl, 1-methyl-2-propynyl, 2-butynyl, 1-methyl-2-butynyl, 1-ethyl-2-butynyl, 3-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1-ethyl-3-butynyl, 2-pentynyl, 1-methyl-2-pentynyl, 3-pentynyl, 1-methyl-3-pentynyl, 2-methyl-3-pentynyl, 4-pentynyl, 1-methyl-4-pentynyl, 2-methyl-4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, heptynyl, 1-methylhexynyl, 2-methylhexynyl, 3-methylhexynyl, 4-methylhexynyl, 5-methylhexynyl, 1-propylbutynyl, 4,4-dimethylpentynyl, octynyl, 1-methylheptynyl, 2-methylheptynyl, 3-methylheptynyl, 4-methylheptynyl, 5-methylheptynyl, 6-methylheptynyl, 1-propylpentynyl, 2-ethylhexynyl, 5,5-dimethylhexynyl, nonynyl, 3-methyloctynyl, 4-methyloctynyl, 5-methyloctynyl, 6-methyloctynyl, 1-propylhexynyl, 2-ethylheptynyl, 6,6-dimethylheptynyl, decynyl, 1-methylnonynyl, 3-methylnonynyl, 8-methylnonynyl, 3-ethyloctynyl, 3,7-dimethyloctynyl, 7,7-dimethyloctynyl, undecynyl, 4,8-dimethylnonynyl, dodecynyl, tridecynyl, tetradecynyl pentadecynyl, 3,7,11-trimethyldodecynyl, hexadecynyl 4,8,12-trimethyltridecynyl, 1-methylpcotadecynyl, 14-methylpentadecynyl, 13,13-dimethyltetradecynyl, heptadecynyl, 15-methylhexadecynyl, octadecynyl, 1-methylheptadecynyl, nonadecynyl, icosynyl or 3,7,11,15-tetramethylhexadecynyl group; preferably a C2-C10 alkynyl group.
In the above formulae the xe2x80x9cC3-C20 alkynyl group interrupted with a hetero atom(s)xe2x80x9d in the definition of R4a and R11 represents the C3-C20 alkynyl groups which are described hereinbefore and which are interrupted with 1 or 2 of the same or different heteroatoms such as a sulfur atom, an oxygen atom or a nitrogen atom. Examples of such groups include an alkyly group which has 3 to 20 carbons and is interrupted with one or two sulfur atoms, such as 1-methylthioethynyl, 2-methylthioethynyl, 1-methylthiopropynyl, 2-methylthiopropynyl, 3-methylthiopropynyl, 2-ethylthioethynyl, 2-methyl-2-methylthioethynyl, 1-methylthiobutynyl, 2-methylthiobutynyl, 3-methylthiobutynyl, 2-ethylthiopropynyl, 3-methyl-3-methylthiopropynyl, 4-methylthiopentynyl, 3-methylthiopentynyl, 2-methylthiopentynyl, 1-methylthiopentynyl, 3,3-dimethylthiobutynyl, 2,2-dimethylthiobutynyl, 1,1-dimethylthiobutynyl, 1-methyl-2-methylthiobutynyl, 1,3-dimethylthiobutynyl, 2,3-dimethylthiobutynyl, 2-ethylthiobutynyl, 1-methylthiohexynyl, 2-methylthiohexynyl, 3-methylthiohexynyl, 4-methylthiohexynyl, 5-methylthiohexynyl, 1-propylthiobutynyl, 4-methyl-4-methylthiopentynyl, 1-methylthioheptynyl, 2-methylthioheptynyl, 3-methylthioheptynyl, 4-methylthioheptynyl, 5-methylthioheptynyl, 6-methylthioheptynyl, 1-propylthiopentynyl, 2-ethylthiohexynyl, 5-methyl-5-methylthiohexynyl, 3-methylthiooctynyl, 4-methylthiooctynyl, 5-methylthiooctynyl, 6-methylthiooctynyl, 1-propylthiohexynyl, 2-ethylthioheptynyl, 6-methylmethioheptynyl, 1-methylthiononynyl, 3-methylthiononynyl, 8-methylthiononynyl, 3-ethylthiooctynyl, 3-methyl-7-methylthiooctynyl, 7,7-methylthiooctynyl, 4-methyl-8-methylthiononynyl, 3,7-dimethyl-11-methylthiododecynyl, 4,8-dimethyl-12-methylthiotridecynyl, 1-methylthiopentadecynyl, 14-methylthiopentadecynyl, 13-methyl-13-methylthiotetradecynyl, 15-methylthiohexadecynyl, 1-methylthioheptadecynyl, and 3,7,11-trimethyl-15-methylthiohexadecynyl; an alkynyl group, which has 3 to 20 carbons and is interrupted with one or two oxygen atoms, such as 1-methyloxyethynyl, 2-methyloxyethynyl, 1-methyloxypropynyl, 2-methyloxypropynyl, 3-methyloxypropynyl, 2-ethyloxyethynyl, 2-methyl-2-methyloxyethynyl, 1-methyloxybutynyl, 2-methyloxybutynyl, 3-methyloxybutynyl, 2-ethyloxypropynyl, 3-methyl-3-methyloxypropynyl, 4-methyloxypentynyl, 3-methyloxypentynyl, 2-methyloxypentynyl, 1-methyloxypentynyl, 3,3-dimethyloxybutynyl, 2,2-dimethyloxybutynyl, 1,1-dimethyloxybutynyl, 1-methyl-2-methyloxybutynyl, 1,3-dimethyloxybutynyl, 2,3-dimethyloxybutynyl, 2-ethyloxybutynyl, 1-methyloxyhexynyl, 2-methyloxyhexynyl, 3-methyloxyhexynyl, 4-methyloxyhexynyl, 5-methyloxyhexynyl, 1-propyloxybutynyl, 4-methyl-4-methyloxypentynyl, 1-methyloxyheptynyl, 2-methyloxyheptynyl, 3-methyloxyheptynyl, 4-methyloxyheptynyl, 5-methyloxyheptynyl, 6-methyloxyheptynyl, 1-propyloxypentynyl, 2-ethyloxyhexynyl, 5-methyl-5-methyloxyhexynyl, 3-methyloxyoctynyl, 4-methyloxyoctynyl, 5-methyloxyoctynyl, 6-methyloxyoctynyl, 1-propyloxyhexynyl, 2-ethyloxyheptynyl, 6-methyl-6-methyloxyheptynyl, 1-methyloxynonynyl, 3-methyloxynonynyl, 8-methyloxynonynyl, 3-ethyloxyoctynyl, 3-methyl-7-methyloxyoctynyl, 7,7-dimethyloxyoctynyl, 4-methyl-8-methyoxynonynyl, 3,7-dimethyl-11-methyloxydodecynyl, 4,8-dimethyl-12-methyloxytridecynyl, 1-methyloxypentadecynyl, 14-methyloxypentadecynyl, 13-methyl-13-methyloxytetradecynyl, 15-methyloxyhexadecynyl, 1-methyloxyheptadecynyl, and 3,7,11-trimethyl-15-methyloxyhexadecynyl; an alkynyl group, which has 3 to 20 carbons and is interrupted with one or two nitrogen atoms, such as 1-(N-methylamino)ethynyl, 2-(N-methylamio)ethynyl, 1-(N-methylamino)propynyl, 2-(N-methylamino)propynyl, 3-(N-methylamino)propynyl, 2-(N-ethylamino)ethynyl, 2-(N-dimethylamino)ethynyl, 1-(N-methylamino)butynyl, 2-(N-methylamio)butynyl, 3-(N-methylamino)butynyl, 2-(N-ethylamino)propynyl, 3-(N,N-dimethylamino)propynyl, 4-(N-methylamino)pentynyl, 3-(N-methylamino)pentynyl, 2-(N-methylamino)pentynyl, 1-(N-methylamino)pentynyl, 3-(N,N-dimethylamino)butynyl, 2-(N,N-dimethylamino)butynyl, 1-(N,N-dimethylamino)butynyl, 1-methyl-2-(N-methylamino)butynyl, 1,3-di(N-methylamino)butynyl, 2,3-di(N-methylamino)butynyl, 2-(N-ethylamino)butynyl, 1-(N-methylamino)hexynyl, 2-(N-methylamino)hexynyl, 3-(N-methylamino)hexynyl, 4-(N-methylamino)hexynyl, 5-(N-methylamino)hexynyl, 1-(N-propylamino)butynyl, 4-methyl-4-(N-methylamino)pentynyl, 1-(N-methylamino)heptynyl, 2-(N-methylamino)heptynyl, 3-(N-methylamino)heptynyl, 4-(N-methylamino)heptynyl, 5-(N-methylamino)heptynyl, 6-(N-methylamino)heptynyl, 1-(N-propylamino)pentynyl, 2-(N-ethylamino)hexynyl, 5-methyl-5-(N-methylamino)hexynyl, 3-(N-methylamino)octynyl, 4-(N-methylamino)octynyl, 5-(N-methylamino)octynyl, 6-(N-methylamino)octynyl, 1-(N-propylamino)hexynyl, 2-(N-ethylamino)heptynyl), 6-methyl-6-(N-methylamino)heptynyl, 1-(N-methylamino)nonynyl, 3-(N-methylamino)nonynyl, 5-(-methylamino)nonynyl, 3-(N-ethylamino)pentynyl, 3-methyl-7-(N-methylamino)octynyl, 7,7-di(N-methylamino)octynyl, 4-methyl-8-(N-methylamino)nonynyl, 3,7-dimethyl-11-(N-methylamino)dodecynyl, 4,8-dimethyl-12-(N-methylamino)tridecynyl, 1-(N-methylamino)pentadecynyl, 14-(N-methylamino)pentadecynyl, 13-methyl-13-(N-methylamino)tetradecynyl, 15-(N-methylamino)hexadecynyl, 1-(N-methylamino)heptadecynyl, and 3,7,11-trimethyl-15(N-methylamino)hexadecynyl; and preferably a C3-C10 alkynyl group interrupted with a heteroatom(s).
In the above formulae the xe2x80x9cC2-C20 alkynyl group substituted with an aryl group(s) or a heteroaryl group(s)xe2x80x9d in the definition of R4a and R11 represents the C2-C20 alkynyl groups described hereinbefore substituted with the same or different 1 to 3 of the aryl groups described hereinbefore or the heteroaryl groups described hereinbefore.
In the above formulae the xe2x80x9cC2-C20 alkenyl groupxe2x80x9d in the definition of R4a and R11 includes, for example, a straight or branched chain alkenyl group having 2 to 20 carbons such as an ethenyl, 2-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 2-ethyl-2-propenyl, 2-butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 1-ethyl-2-butenyl, 3-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 1-ethyl-3-butenyl, 2-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 4-pentenyl, 1-methylpentenyl, 2-methyl-4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, heptenyl, 1-methylhexenyl, 2-methylhexenyl, 3-methylhexenyl, 4-methylhexenyl, 5-methylhexenyl, 1-propylbutenyl, 4,4-dimethylpentenyl, octenyl, 1-methylheptenyl, 2-methylheptenyl, 3-methylheptenyl, 4-methylheptenyl, 5-methylheptenyl, 6-methylheptenyl, 1-propylpentenyl, 2-ethylhexenyl, 5,5-dimethylhexenyl, nonenyl, 3-methyloctenyl, 4-methyloctenyl, 5-methyloctenyl, 6-methyloctenyl, 1-propylhexenyl, 2-ethylheptenyl, 6,6-dimethylheptenyl, decenyl, 1-methylnonenyl, 3-methylnonenyl, 8-methylnonenyl, 3-ethyloctenyl, 3,7-dimethyloctenyl, 7,7-dimethyloctenyl undecenyl, 4,8-dimethylnonenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, 3,7,11-trimethyldodecenyl, hexadecenyl, 4,8,12-trimethyltridecenyl, 1-methylpentadecenyl, 14-methylpentadecenyl, 13,13-dimethyltetradecenyl, heptadecenyl, 15-methylhexadecenyl, octadecenyl, 1-methylheptadecenyl, nonadecenyl, icosenyl and 3,7,11,15-tetramethylhexadecenyl group; preferably a C2-C10 alkenyl group.
In the above formulae the xe2x80x9cC3-C20 alkenyl group interrupted with a hetero atom(s)xe2x80x9d in the definition of R4a and R11 represents the C3-C20 alkenyl groups which are described hereinbefore and interrupted with the same or different 1 or 2 of heteroatoms such as a sulfur atom, an oxygen atom or a nitrogen atom. Examples of such a group include an alkenyl group which has 3 to 20 carbons and is interrupted with one or two sulfur atoms, such as 1-methylthioethenyl, 2-methylthioethenyl, 1-methylthiopropenyl, 2-methylthiopropenyl, 3-methylthiopropenyl, 2-ethylthioethenyl, 2-methyl-2-methylthioethenyl, 1-methylthiobutenyl, 2-methylthiobutenyl, 3-methylthiobutenyl, 2-ethylthiopropenyl, 3-methyl-3-methylthiopropenyl, 4-methylthiopentenyl, 3-methylthiopentenyl, 2-methylthiopentenyl, 1-methylithiopentenyl, 3,3-dimethylthiobutenyl, 2,2-dimethylthiobutenyl, 1,1-dimethylthiobutenyl, 1-methyl-2-methylthiobutenyl, 1,34-dimethylthiobutenyl, 2,3-dimethylthiobutenyl, 2-ethylthiobutenyl, 1-methylthiohexenyl, 2-methylthiohexenyl, 3-methylthiohexenyl, 4-methylthiohexenyl, 5-methylthiohexenyl, 1-propylthiobutenyl, 4-methyl-4-methylthiopentenyl, 1-methylthioheptenyl, 2-methylthioheptenyl, 3-methylthioheptenyl, 4-methylthioheptenyl, 5-methylthioheptenyl, 6-methylthioheptenyl, 1-propylthiopentenyl, 2-ethylthiohexenyl, 5-methyl-5-methylthiohexenyl, 3-methylthiooctenyl, 4-methylthiooctenyl, 5-methylthiooctenyl, 6-methylthiooctenyl, 1-propylthiohexenyl, 2-ethylthioheptenyl, 6-methyl-6-methylthioheptenyl, 1-methylthiononenyl, 3-methylthiononenyl, 8-methylthiononenyl, 3-ethylthiooctenyl, 3-methyl-7-methylthiooctenyl, 7,7-dimethylthiooctenyl, 4-methyl-8-methylthiononenyl, 3,7-methyl-11-methylthiododecenyl, 4,8-dimethyl-12-methylthiotridecenyl, 1-methylthiopentadecenyl, 14-methylthiopentadecenyl, 13-methyl-13-methylthiotetradecenyl, 15-methylthiohexadecenyl, 1-methylthioheptadecenyl, and 3,7,11-trimethyl-15-methylthiohexadecenyl; an alkenyl group, which has 3 to 20 carbons and interrupted with one or two oxygen atoms, such as 1-methyloxyethenyl, 2-methyloxyethenyl, 1-methyloxypropenyl, 2-methyloxypropenyl, 3-methyloxypropenyl, 2yloxyethenyl, 2-methyl-2-methyloxyethenyl, 1-methyloxybutenyl, 2-methyloxybutenyl, 3-methyloxybutenyl, 2-ethyloxypropenyl, 3-methyl-3-methyloxypropenyl, 4-methyloxypentenyl, 3-methyloxypentenyl, 2-methyloxypentenyl, 1-methyloxypentenyl, 3,3-dimethyloxybutenyl, 2,2-dimethyloxybutenyl, 1,1-dimethyloxybutenyl, 1-methyl-2-methyloxybutenyl, 1,3-dimethyloxybutenyl, 2,3-dimethyloxybutenyl, 2-ethyloxybutenyl, 1-methyloxyhexenyl, 2-methyloxyhexenyl, 3-methyloxyhexenyl, 4-methyloxyhexenyl, 5-methyloxyhexenyl, 1-propyloxybutenyl, 4-methyl-4-methyloxypentenyl, 1-methyloxyheptenyl, 2-methyloxyheptenyl, 3-methyloxyheptenyl, 4-methyloxyheptenyl, 5-methyloxyheptenyl, 6-methyloxyheptenyl, 1-propyloxypentenyl, 2-ethyloxyhexenyl, 5-methyl-5-methyloxyhexenyl, 3-methyloxyoctenyl, 4-methyloxyoctenyl, 5-methyloxyoctenyl, 6-methyloxyoctenyl, 1-propyloxyhexenyl, 2-ethyloxyheptenyl, 6-methyl-6-methyloxyheptenyl, 1-methyloxynonenyl, 3-methyloxynonenyl, 8-methyloxynonenyl, 3-ethyloxyoctenyl, 3-methyl-7-methyloxyoctenyl, 7,7-dimethyloxyoctenyl, 4-methyl-8-methyloxynonenyl, 3,7-dimethyl-11-methyloxydodecenyl, 4,8-dimethyl-12-methyloxytridecenyl, 1-methyloxypentadecenyl, 14-methyloxypentadeccnyl, 13-methyl-13-methyloxytetradecenyl, 15-methyloxyhexadecenyl, 1-methyloxyheptadecenyl, and 3,7,11-trimethyl-15-methyloxyhexadecenyl; an alkenyl group which has 3 to 20 carbons and is interrupted with one or two nitrogen atoms, such as 1-(N-methylamino)ethenyl, 2-(N-methylamino)ethenyl, 1-(N-methylamino)propenyl, 2-(N-methylamino)propenyl, 3-(N-methylamino)propenyl, 2-(N-ethylamino)ethenyl, 2-(N,N-dimethylamino)ethenyl, 1-(N-methylamino)butenyl, 2-(N-methylamino)butenyl, 3-(N-methylamino)butenyl, 2-(N-ethylamino)propenyl, 3-(N,N-dimethylamino)propenyl, 4-(N-methylamino)pentenyl, 3-(N-methylamino)pentenyl, 2-(N-methylamino)pentenyl, 1-(N-methylamino)pentenyl, 3-(N,N-dimethylamino)butenyl, 2-(N,N-diethylamino)butenyl, 1-(N,N-dimethylamino)butenyl, 1-methyl-2-(N-methylamino)butenyl, 1,3-di(N-methylamino)butenyl, 2,3-di(N-methylamino)butenyl, 2-(N-ethylamino)butenyl, 1-(N-methylamino)hexenyl, 2-(N-methylamino)hexenyl, 3-(N-methylamino)hexenyl, 4-(N-methylamino)hexenyl, 5-(N-methylamino)hexenyl, 1-(N-propylamino)butenyl, 4-methyl-4-(N-methylamino)pentenyl, 1-(N-methylamino)heptenyl, 2-(N-methylamino)heptenyl, 3-(N-methylamio)heptenyl, 4-(N-methylamino)heptenyl, 5-(N-methylamino)heptenyl, 6-(N-methylamino)heptenyl, 1-(N-propylamino)pentenyl, 2-(N-ethylamino)hexenyl, 5-methyl-5-(N-methylamino)hexenyl, 3-(N-methylamino)octenyl, 4-(N-methylamino)octenyl, 5-(N-methylamino)octenyl, 6-(N-methylamino)octenyl, 1-(N-propylamino)hexenyl, 2-ethylamino)heptenyl, 6-methyl-6-(N-methylamino)heptenyl, 1-(N-methylamino)nonenyl, 3-(N-methylamino)nonenyl, 8-(N-methylamino)nonenyl, 3-(N-ethylamino)octenyl, 3-methyl-7-(N-methylamino)octenyl, 7,7-di(N-methylamino)octenyl, 4-methyl-8-(N-methylamino)nonenyl, 3,7-dimethyl-11-(N-methylamino)dodecenyl, 4,8 dimethyl-12-(N-methylamino)tridecenyl, 1-(N-methylamino)pentadecenyl, 14-(N-methylamino)pentadecenyl, 13-methyl-13-(N-methylamino)tetradecenyl, 15-(N-methylamino)hexadecenyl, 1-(N-methylamino)heptadecenyl, and 3,7,11-trimethyl-15-(N-methylamino)hexadecenyl; and preferably a C3-C10 alkenyl group interrupted with a heteroatom(s).
In the above formulae the xe2x80x9cC2-C20 alkenyl group substituted with an aryl group(s) or a heteroaryl group(s)xe2x80x9d in the definition of R4a and R11 represents the C2-C20 alkenyl groups described hereinbefore substituted with the same or different 1 to 3 of the aryl groups described hereinbefore or the heteroaryl groups described hereinbefore.
In the above formulae the xe2x80x9cC2-C20 alkyl group which is substituted with an aryl group(s) or a heteroaryl group(s) and interrupted with a heteroatom(s)xe2x80x9d in the definition of R4a and R11, represents the C2-C20 alkyl groups interrupted with a heteroatom(s), described hereinbefore and substituted with the same or different 1 to 3 of the aryl groups described hereinbefore or the heteroaryl groups described hereinbefore.
The lipase employed in this invention is not particularly limited and the preferred lipase is different depending on the starting material, however, is typically obtained from Pseudomonas sp., Pseudomonas fluorescens, Pseudomonas cepacia, Chromobacterium viscosum, Aspergillus niger, Aspergillus oryzae, Candida antarctica, Candida cylindracea, Candida lipolytica, Candida rugosa, Candida utilis, Penicillium roqueforti, Rhizopus arrhizus, Rhizopus delemar, Rhizopus javanicus, Rhizomucor miehei, Rhizopus niveus, Humicola lanuginosa, Mucor Javanicus, Mucor miehei, Thermus aquaticus, Thermus flavus, Thermus thermophilus or the like; or human pancreas, hog pancreas, porcine pancreas or wheat germ. Partially or completely purified enzyme moiety and fixed enzyme can be employed and the most preferred lipase is fixed Pseudomonas sp. [for example, immobilized lipase from Pseudomonas sp. (TOYOBO Kabusiki Kaisya)].
Preferred vinyl ester derivatives of the carboxylic acid of formula (XLIII, R11COOCHxe2x95x90CH2) employed in this invention are different depending on the starting material, however they are typically a vinyl ester of a straight chain aliphatic acid such as the vinyl ester of n-hexanoic acid, vinyl ester of n-heptanoic acid, vinyl ester of n-pentanoic acid, vinyl ester of acetic acid or the like; and the most preferred one is the vinyl ester of n-hexanoic acid.
When the compound of formula (I) has a basic group such as amino group, the pharmaceutically acceptable salt can be prepared by the reaction of compound (I) with an acid. When the compound of formula (I) has a carboxy group the pharmaceutically acceptable salt can be prepared by the reaction of compound (I) with a base.
The preferred salts based on a basic group include a hydrohalogenic acid salt such as a hydrofluoride, hydrochloride, hydrobromide or hydroiodide; an inorganic acid salt such as a nitrate, perchlorate, sulfate or phosphate; a lower alkanesulfonic acid salt such as a methanesulfonate, trifluoromethanesulfonate or ethanesulfonate; an aryl sulfonic acid salt such as a benzenesulfonate or ptoluenesulfonate; an organic acid salt such as an acetate, maleate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate, maleate or the like; an amino acid salt such as a glycine salt, lysine salt, arginine salt, ornithine salt, glutamic acid salt or aspartic acid salt and most preferably an organic acid salt.
On the other hand the preferred salts based on an acid group includes an alkali metal salt such as a sodium salt, potassium salt or lithium salt; an alkaline earth metal salt such as a calcium salt or magnesium salt; a metal salt such as an aluminum salt or iron salt; an inorganic salt such as an ammonium salt; an amine salt such as a t-octylamine salt, benzylamine salt, morpholine salt, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglucamine salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N,Nxe2x80x2-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzylphenethylamine salt, piperazine salt, tetramethylammonium salt or tri(hydroxymethyl)aminomethane salt; and an amino acid salt such as a glycine salt, lysine salt, argime salt, ornithine salt, glutatnic acid salt or aspartic acid salt
When the Compound (I), a pharmaceutically acceptable salt thereof, an ester thereof or other derivative thereof are allowed to stand so that they are opened to the atmosphere or are recrystallized, they may absorb water and water may be attached to them to form a hydrate.
The salts of the present invention encompass such hydrates.
The compounds of formula (I), pharmaceutically acceptable salts thereof, esters thereof or other derivatives thereof have an asymmetric carbon (s) and can exist as optical isomer(s). In this invention a single optical isomer and a mixture of optical isomers are represented by the single chemical formula (I). The present invention encompasses the optical isomers individually and mixtures thereof in optional ratios. For example, the compounds of formula (I), pharmaceutically acceptable salts thereof, esters thereof or other derivatives thereof have the following partial chemical formula wherein the xe2x80x94NR1R2 group is attached to an asymmetric carbon and the preferred absolute configuration at this asymmetric carbon is the R configuration. 
In the above formulae the xe2x80x9cesterxe2x80x9d refers to an ester of a compound of formula (I) which has a group capable of being esterified. The ester includes the ester of a hydroxyl group and the ester of a carboxy group. Each ester residual group belongs to a general protecting group in chemical reactions or a protecting group capable of being removed by a biological process such as hydrolysis in vivo.
The xe2x80x9cgeneral protecting group in chemical reactionxe2x80x9d can be cleaved by a chemical process such as hydrogenolysis, hydrolysis, electrolysis or photolysis.
The xe2x80x9cgeneral protecting group in chemical reactionsxe2x80x9d and the xe2x80x9cprotecting group capable of being removed by a biological process such as hydrolysis in vivoxe2x80x9d in the esters of a hydroxyl group have the same meaning as that described above for a hydroxyl protecting group.
The xe2x80x9cgeneral protecting group in chemical reactionsxe2x80x9d in the ester of a carboxyl group preferably includes a lower alkyl group described hereinbefore; a lower alkenyl group such as ethenyl, 1-propenyl, 2-propenyl, 1-methyl-2-propenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 1-methyl-2-butenyl, 1-methyl-1-butenyl, 3-methyl-2-butenyl, 1-ethyl-2-butenyl, 3-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 1-ethyl-3-butenyl, 1-pentenyl, 2-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 4-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl or 5-hexenyl; a lower alkynyl group such as ethynyl, 2-propynyl, 1-methyl-2-propynyl, 2-butynyl, 1-methyl-2-butynyl, 1-ethyl-2-butynyl, 3-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1-ethyl-3-butynyl, 2-pentynyl, 1-methyl-2-pentynyl, 3-pentynyl, 1-methyl-3-pentynyl, 2-methyl-3-pentynyl, 4-pentynyl, 1-methyl-4-pentynyl, 2-methyl-4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl or 5-hexynyl; a halogenated lower alkyl group described hereinbefore; a hydroxy lower alkyl group such as 2-hydroxyethyl, 2,3-dihydroxypropyl, 3-hydroxypropyl, 3,4-dihydroxybutyl or 4-hydroxybutyl; lower aliphatic acyl-lower alkyl group such as acetylmethyl; an aralkyl group described hereinbefore; or a silyl group described hereinbefore.
The xe2x80x9cprotecting group capable of being removed by a biological process such as hydrolysis in vivoxe2x80x9d can be cleaved by a biological process such as hydrolysis in the human body to afford a free acid or a salt thereof. Whether a derivative of formula (I) has such a protecting group can be easily determined. The derivative under investigation is administered intravenously to a test animal such as a mouse or a rat and the body fluids of the test animal are thereafter studied. If the parent compound or a pharmacologically acceptable salt thereof is detected in the body fluids of the test animal, the derivative under investigation is judged to have such a group. The xe2x80x9cprotecting group capable of being removed by a biological process such as hydrolysis in vivoxe2x80x9d preferably includes a lower alkoxy lower alkyl group such as methoxyethyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyl, 1-(isopropoxy)ethyl, 2-methoxyethyl, 2-ethoxyethyl, 1,1-dimethyl-1-methoxyethyl, ethoxymethyl, n-propoxymethyl, isopropoxymethyl, n-butoxymethyl or t-butoxymethyl; a lower alkoxy lower alkoxy lower alkyl group such as 2-methoxyethoxymethyl; an aryloxy lower alkyl group such as phenoxymethyl; a halogenated lower alkoxy lower alkyl group such as 2,2,2-trichloroethoxymethyl or bis(2-chloroethoxy)methyl; a lower alkoxycarbonyl lower alkyl group such as methoxycarbonylmethyl; a cyano lower alkyl group such as cyanomethyl or 2-cyanoethyl; a lower alkylthiomethyl group such as methylthiomethyl or ethylthiomethyl; an arylthiomethyl group such as phenylthiomethyl or naphthylthiomethyl; a lower alkyl optionally substituted with a halogen atom(s) sulfonyl lower alkyl group such as 2-methanesulfonylethyl or 2-trifluoromethanesulfonylethyl; an arylsulfonyl lower alkyl group such as 2-benzenesulfonylethyl or 2-toluenesulfonylethyl; a 1-(acyloxy) lower alkyl group described hereinbefore; a phthalidyl group described hereinbefore; an aryl group described hereinbefore; a lower alkyl group described hereinbefore; a carboxyalkyl group such as carboxymethyl; and an amide-formation residual group of an amino acid such as phenylalanine.
When the compound of formula (I) in this invention has an amino group and/or a carboxyl group, such a compound can be converted to a derivative other than a pharmacologically acceptable salt or an ester described hereinbefore. The xe2x80x9cother derivativexe2x80x9d refers to such a derivative, for example, an amide derivative such as an acyl group.
Typical examples of compounds of formula (I) in this invention are listed in the following Table 1 and 2. Typical examples of compound of formula (La) and (La-1) in this invention are listed in Table 3 and 4. The present invention is not limited to these examples.
The following abbreviation are used in these lists:
Ac: acetyl group; Boc: t-butoxycarbonyl group; Bpyrr: benzopyrrolyl group; Bu: butyl group; iBu: isobutyl group; Bz: benzyl group; Bzt: benzothienyl group; Et: ethyl group; Fur: furyl group; cHx: cyclohexyl group; Me: methyl group; Np(1): naphthalen-1-yl group; Np(2): naphthalen-2-yl group; Ph: phenyl group; cPn: cyclopentyl group; Pr: propyl group; iPr: isopropyl group; Pyr: pyridyl group; TBDMS: t-butyldimethylsilyl group; and The: thienyl group.
Preferred compounds in Tables 1 and 2 are those of Exemplification compounds numbers 1-19, 1-23 to 1-32, 1-36 to 1-45, 1-49 to 1-58, 1-62 to 1-71, 1-75 to 1-84, 1-88 to 1-102, 1-106 to 1-156, 1-160 to 1-214, 1-218 to 1-268, 1-272 to 1-322, 1-325 to 1-334, 1-338 to 1-347, 1-351 to 1-360, 1-364 to 1-373, 1-377 to 1-386, 1-390 to 1-404, 1-408 to 1-458, 1-462 to 1-513, 1-517 to 1-526, 1-530 to 1-544, 1-548 to 1-598, 1-602 to 1-657, 1-670, 1-674 to 1-683, 1-696, 1-700 to 1-717, 1-721 to 1-730, 1-734 to 1-743, 1-747 to 1-756, 1-760 to 1-774, 1-778 to 1-828, 1-832 to 1-886, 1-890 to 1-940, 1-944 to 1-993, 1-977 to 1-1006, 1-1010 to 1-1019, 1-1045, 1-1049, 1-1058, 1-1062 to 1-1076, 1-1080 to 1-1130, 1-1134 to 1-1185, 1-1189 to 1-1198, 1-1202 to 1-1208, 1-1212 to 1-1216, 1-1220to 1-1270, 1-1274 to 1-1331, 1-1335 to 1-1344, 1348 to 1-1357, 1-1361 to 1-1370, 1-1374 to 1-1387, 1-1391 to 1-1400, 1-1404 to 1-1418, 1-1422 to 1-1472, 1-1476 to 1-1527, 1-1531 to 1-1540, 1-1544 to 1-1558, 1-1562 to 1-1612, 1-1616 to 1-1673, 1-1677 to 1-1686, 1-1690 to 1-1699, 1-1703 to 1-1712, 1-1716 to 1-1729, 1-1733 to 1-1744, 1-1748 to 1-1767, 1-1772 to 1-1793, 1-1797 to 1-1818, 1-1824 to 1-1846, 1-1850 to 1-1869, 1-1872, 1-1876, 1-1880, 1-1884, 1-1888 to 1-1892, 1-1896, 1-1900, 1-1908 to 1-1913, 1-1917 to 1-1939, 1-1943 to 1-1966, 1-1970 to 1-1991, 1-1995 to 1-2013, 1-2017, 1-2021, 1-2025, 1-2029, 1-2033, 1-2037 to 1-2042, 1-2045 to 1-2068, 1-2072 to 1-2089, 1-2093, 1-2097, 1-2101, 1-2105, 1-2109, 1-2113, 1-2117, 1-2121, 1-2125, 1-2129, 1-2133, 1-2135, 1-2139 to 1-2158, 1-2161 to 1-2164, 1-2184 to 1-2346, 2-9 to 2-18, 2-22 to 2-43, 247 to 2-70, 2-74 to 2-96, 2-100 to 2-219, 2-142, 2-146, 2-150, 2-154, 2-158 to 2-163, 2-167 to 2-183, 2-185 to 2-189, 2-193 to 2-216, 2-220 to 2-241, 2-245 to 2-263, 2-267, 2-271, 2-275, 2-279, 2-283, 2-287 to 2-292, 2-296 to 2-318, 2-322 to 2-338, 2-343, 2-347, 2-351, 2-371, 2-375 to 2-377, 2-381 to 2-407.
More preferred compounds are those of Exemplification compounds numbers 1-19, 1-32, 1-36 to 1-45, 1-57, 1-62 to 1-71, 1-84, 1-88, 1-97 to 1-100, 1-152 to 1-154, 1-160 to 1-214, 1-218to 1-227, 1-264 to 1-268, 1-272 to 1-322, 1-334, 1-347, 1-360, 1-373, 1-386, 1-390 to 1-402, 1-454 to 1-458, 1-462 to 1-513, 1-526, 1-530 to 1-542, 1-594 to 1-598, 1-602 to 1-653, 1-743, 1-756, 1-760 to 1-768, 1-770 to 1-774, 1-778 to 1-828, 1-832 to 1-886, 1-890 to 1-940, 1-944 to 1-993, 1-1045, 1-1058, 1-1062 to 1-1074, 1-1126 to 1-1130, 1-1134 to 1-1185, 1-1198, 1-1202 to -1208, 1-1212, 1-1213, 1-1214, 1-1266 to 1270, 1-1274 to 1331, 1-1344, 1-1348 to 1-1357, 1-1370, 1-1374 to 1-1387, 1-1400, 1-1404 to 1-1416, 1-1468 to 1-1472, 1-1476 to 1-1527, 1-1540, 1-1544 to 1-1556, 1-1608 to 1-1612, 1-1616 to 1-1666, 1-1729, 1-1742, 1-1744, 1-1759 to 1-1767, 1-1789 to 1-1793, 1-1797 to 1-1818, 1-1842 to 1-1846, 1-1900, 1-1908 to 1-1913, 1-1935 to 1-1939, 1-1943 to 1-1966, 1-1987 to 1-1991, 1-2013, 1-2017, 1-2029, 1-2033, 1-2037 to 1-2042, 1-2064 to 1-2068, 1-2072 to 1-2089, 1-2093, 1-2097, 1-2101, 1-2105, 1-2109, 1-2129, 1-2133, 1-2135, 1-2184 to 1-2346, 2-11 to 2-18, 2-39 to 2-43, 2-47 to 2-70, 2-185 to 2-189, 2-193 to 2-216, 2-287 to 2-292, 2-338, 2-343, 2-347, 2-351.
More preferred compounds are those of Exemplification compounds numbers 1-45, 1-71, 1-84, 1-88, 1-97 to 1-100, 1-152 to 1-154, 1-160 to 1-206, 1-209 to 1-212, 1-264 to 1-266, 1-334, 1-373, 1-386, 1-390 to 1402, 1454 to 1-458, 1-462 to 1-485, 1-509, 1-510, 1-513, 1-526, 1-530 to 1-542, 1-594 to 1-598, 1-602 to 1-613, 1-649, 1-650, 1-743, 1-756, 1-760 to 1-768, 1-770 to 1-772, 1-824 to 1-828, 1-884, 1-936, 1-1045, 1-1058, 1-1062 to 1-1074, 1-1126 to 1-1130, 1-1134 to 1-1145, 1-1148 to 1-1151, 1-1162, 1-1163, 1-1179 to 1-1182, 1-1185, 1-1198, 1-1202 to 1-1208, 1-1212, 1-1213, 1-1214, 1-1266 to 1-1270, 1-1274 to 1-1285, 1-1288 to 1-1291, 1-1319 to 1-1322, 1-1329 to 1-1331, 1-1344, 1-1348 to 1-1357, 1-1370, 1-1387, 1-1400, 1-1404 to 1-1416, 1-1468 to 1-1472, 1-1476 to 1-1487, 1-1490 to 1-1493, 1-1504, 1-1505, 1-1521 to 1-1524, 1-1527, 1-1540, 1-1544 to 1-1556, 1-1608 to 1-1612, 1-1616 to 1-1627, 1-1663, 1-1664, 1-1729, 1-1742, 1-1744, 1-1761 to 1-1766, 1-1789 to 1-1791, 1-1815 to 1-1818, 1-1900, 1-1909, 1-1962, 1-2064 to 1-2066, 1-2089, 1-2093, 1-2097, 1-2105, 1-2133, 1-2216 to 1-2288, 1-2290 to 1-2346.
Still more preferred compounds in Tables 1 and 2 are those exemplification compounds numbers:
1-71: 2-amino-2-methyl-4-[5-(4-cyclohexylbutyl)thiophen-2-yl]butan-1-ol,
1-84: 2-amino-2-methyl-4-[5-(4-phenylbutyl)thiophen-2-yl]butan-1-ol,
1-98: 2-amino-2-methyl-4-[5-(5-cyclohexylpentyl)thiophen-2-yl]butan-1-ol,
1-152: 2-amino-2-methyl-4-[5-(5-phenylpentyl)thiophen-2-yl]butan-1-ol,
1-210: 2-amino-2-methyl-4-[5-(6-cyclohexylhexyl)thiophen-2-yl]butan-1-ol,
1-264: 2-amino-2-methyl-4-[5-(6-phenylhexyl)thiophen-2-yl]butan-1-ol,
1-373: 2-amino-2-methyl-4-[5-(3-cyclohexyloxypropyl)thiophen-2-yl]butan-1-ol,
1-386: 2-amino-2-methyl-4-[5-(3-phenoxypropyl)thiophen-2-yl]butan-1-ol,
1-400: 2-amino 2-methyl-4-[5-(4-cyclohexyloxybutyl)thiophen-2-yl]butan-1-ol,
1-454: 2-amino-2-methyl-4-[5-(4-phenoxybutyl)thiophen-2-yl]butan-1-ol,
1-509: 2-amino-2-methyl-4-[5-(5-cyclohexyloxypentyl)thiophen-2-yl]butan-1-ol,
1-510: 2-amino-2-methyl-4-[5-(5-phenoxypentyl)thiophen-2-yl]butan-1-ol,
1-513: 2-amino-2-methyl-4-[5-(3-cyclohexylmethoxypropyl)thiophen-2-yl]butan-1-ol,
1-743: 2-amino-2-methyl-4-[5-(4-cyclohexylbut-1-ynyl)thiophen-2-yl]butan-1-ol,
1-756: 2-amino-2-methyl-4-[5-(4-phenylbut-1-ynyl)thiophen-2-yl]butan-1-ol,
1-770: 2-amino-2-methyl-4-[5-(5-cyclohexylpent-1-ynyl)thiophen-2-yl]butan-1-ol,
1-824: 2-amino-2-methyl-4-[5-(5-phenylpent-1-ynyl)thiophen-2-yl]butan-1-ol,
1-882: 2-amino-2-methyl-4-[5-(6-cyclohexylhex-1-ynyl)thiophen-2-yl]butan-1-ol,
1-936: 2-amino-2-methyl-4-[5-(6-phenylhex-1-ynyl)thiophen-2-yl]butan-1-ol,
1-1045: 2-amino-2-methyl-4-[5-(3-cyclohexyloxypropynyl)thiophen-2-yl]butan-1-ol,
1-1058: 2-amino-2-methyl-4-[5-(3-phenoxypropynyl)thiophen-2-yl]butan-1-ol,
1-1072: 2-amino-2-methyl-4-[5-(4-cyclohexyloxybut-1-ynyl)thiophen-2-yl]butan-1-ol,
1-1126: 2-amino-2-methyl-4-[5-(4-phenoxybut-1-ynyl)thiophen-2-yl]butan-1-ol,
1-1181: 2-amino-2-methyl-4-[5-(5-cyclohexyloxypent-1-ynyl)thiophen-2-yl]butan-1-ol,
1-1182: 2-amino-2-methyl-4-[5-(5-phenoxypent-1-ynyl)thiophen-2-yl]butan-1-ol,
1-1185: 2-amino-2-methyl-4-[5-(3-cyclohexylmethoxypropynyl)thiophen-2-yl]butan-1-ol,
1-1329: 2-amino-2-methyl 4-[5-(4-cyclohexylbutanoyl)thiophen-2-yl]butan-1-ol,
1-1330: 2-amino-2-methyl-4-[5-(4-phenylbutanoyl)thiophen-2-yl]butan-1-ol,
1-1331: 2-amino-2-methyl-4-[5-(5-cyclohexylpentanoyl)thiophen-2-yl]butan-1-ol,
1-1344: 2-amino-2-methyl-4-[5-(5-phenylpentanoyl)thiophen-2-yl]butan-1-ol,
1-1357: 2-amino-2-methyl-4-[5-(6-cyclohexylhexanoyl)thiophen-2-yl)butan-1-ol,
1-1370: 2-amino-2-methyl-4-[5-(6-phenylhexanoyl)thiophen-2-yl]butan-1-ol,
1-1387: 2-amino-2-methyl-4-[5-(3-cyclohexyloxypropanoyl)thiophen-2-yl]butan-1-ol,
1-1400: 2-amino-2-methyl-4-[5-(3-phenoxypropanoyl)thiophen-2-yl]butan-1-ol,
1-1414: 2-amino-2-methyl-4-[5-(4-cyclohexyloxybutanoyl)thiophen-2-yl]butan-1-ol,
1-1468: 2-amino-2-methyl-4-[5-(4-phenoxybutanoyl)thiophen-2-yl]butan-1-ol,
1-1523: 2-amino-2-methyl-4-[5-(5-cyclohexyloxypentanoyl)thiophen-2-yl]butan-1-ol,
1-1524: 2-amino-2-methyl-4-[5-(5-phenoxypentanoyl)thiophen-2-yl]butan-1-ol,
1-1527: 2-amino-2-methyl-4-[5-(3-cyclohexylmethoxypropanoyl)thiophen-2-yl]butan-1-ol,
1-1729: 2-amino-2-methyl-4-[5-(4-cyclohexyhnethoxyphenyl)thiophen-2-yl]butan-1-ol,
1-1742: 2-amino-2-methyl-4-[5-(4-cyclohexylethoxyphenyl)thiophen-2-yl]butan-1-ol,
1-1744: 2-amino-2-methyl-4-[5-(4-benzyloxyphenyl)thiophen-2-yl]butan-1-ol,
1-1761: 2-amino-2-ethyl-4-[5-(4-cyclohexylbutyl)thiophen-2-yl]butan-1-ol,
1-1764: 2-amino-2-ethyl-4-[5-(5-cyclohexylpentyl)thiophen-2-yl]butan-1-ol,
1-1816: 2-amino-2-ethyl-4-[5-(6-cyclohexylhexyl)thiophen-2-yl]butan-1-ol,
1-1900: 2-amino-2-ethyl-4-[5-(4-cyclohexylbut-1-ynyl)thiophen-2-yl]butan-1-ol,
1-1909: 2-amino-2-ethyl-4-[5-(5-cyclohexylpent-1-ynyl)thiophen-2-yl]butan-1-ol,
1-1962: 2-amino-2-ethyl-4-[5-(6-cyclohexylhex-1-ynyl)thiophen-2-yl]butan-1-ol,
1-2089: 2-amino-2-ethyl-4-[5-(4-cyclohexylbutanoyl)thiophen-2-yl]butan-1-ol,
1-2097: 2-amino-2-ethyl-4-[5-(5-cycloheylpentanoyl)thiophen-2-yl]butan-1-ol,
1-2105: 2-amino-2-ethyl-4-[5-(6-cyclohexylhexanoyl)thiophen-2-yl]butan-1-ol,
1-463: 2-amino-2-methyl-4-{5-[4-(4-fluorophenoxy)butyl]thiophen-2-yl}butan-1-ol,
1-479: 2-amino-2-methyl-4-{5-[4-(4-methoxyphenoxy)butyl]thiophen-2-yl}butan-1-ol,
1-594: 2-amino-2-methyl-4-[5-(4-benzyloxybutyl)thiophen-2-yl]butan-1-ol,
1-760: 2-amino-2-methyl-4-{5-[4-(4-fluorophenyl)but-1-yny]thiophen-2-yl}butan-1-ol,
1-761: 2-amino-2-methyl-4-{5-[4-(4-methylphenyl)but-1-ynyl]thiophen-2-yl}butan-1-ol,
1-762: 2-amino-2-methyl-4-{5-[4-(4-ethylphonyl)but-1-ynyl]thiophen-2-yl}butan-1-ol,
1-763: 2-amino-2-methyl-4-{5-[4-(4-trifluoromethylphenyl)but-1-ynyl]thiophen-2-yl}butan-1-ol,
1-764: 2-amino-2-methyl-4-{5-[4-(4-methoxyphenyl)but-1-ynyl]thiophen-2-yl}butan-1-ol,
1-765: 2-amino-2-methyl-4-{5-[4-(4-ethoxyphenyl)but-1-ynyl]thiophen-2-yl}butan-1-ol,
1-766: 2-amino-2-methyl-4-{5-[4-(4-methylthiophenyl)but-1-ynyl]thiophen-2-yl}butan-1-ol,
1-832: 2-amino-2-methyl-4-{5-[5-(3-fluorophenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol,
1-833: 2-amino-2-methyl-4-{5-[5-(4-fluorophenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol,
1-834: 2-amino-2-methyl-4-{5-[5-(4-chlorophenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol,
1-836: 2-amino-2-methyl-4-{5-[5-(3-methylphenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol,
1-837: 2-amino-2-methyl-4-{5-[5-(4-methylphenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol,
1-846: 2-amino-2-methyl-4-{5-[5-(3-trifluoromethylphenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol,
1-847: 2-amino-2-methyl-4-{5-[5-(4-trifluorophenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol,
1-848: 2-amino-2-methyl-4-{5-[5-(3-methoxyphenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol,
1-849: 2-amino-2-methyl-4-{5-[5-(4-methoxyphenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol,
1-860: 2-amino-2-methyl-4-{5-[5-(3-methylthiophenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol,
1-861: 2-amino-2-methyl-4-{5-[5-(4-methylphenyl]pent-1-ynyl]thiophen-2-yl}butan-1-ol,
1-877: 2-amino-2-methyl-4-{5-[5-(3,4-dimethylphenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol,
1-878: 2-amino-2-methyl-4-{5-[5-(3,5-dimethylphenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol,
1-1050: 2-amino-2-methyl-4-{5-[3-(4-methylycyohexyloxy)propynyl]thiophen-2-yl}butan-1-ol,
1-1062: 2-amino-2-methyl-4-{5-[3-(4-fluorophenoxy)propynyl]thiophen-2-yl}butan-1-ol,
1-1063: 2-amino-2-methyl-4-{5-[3-(4-methylphenoxy)propynyl]thiophen-2-yl}butan-1-ol,
1-1064: 2-amino-2-methyl-4-{5-[3-(4-ethylphenoxy)propynyl]thiophen-2-yl}butan-1-ol,
1-1065: 2-amino-2-methyl-4-{5-[3-(4-trifluoromethylphenyl)propynyl]thiophen-2-yl}butan-1-ol,
1-1066: 2-amino-2-methyl-4-{5-[3-(4-methoxyphenoxy)propynyl]thiophen-2-yl}butan-1-ol,
1-1067: 2-amino-2-methyl-4-{5-[3-(4-methoxyphenoxy)propynyl]thiophen-2-yl}butan-1-ol,
1-1068: 2-amino-2-methyl-4-{5-[3-(4-methylthiophenoxy)propynyl]thiophen-2-yl}butan-1-ol,
1-1134: 2-amino-2-methyl-4-{5-[4-(3-fluorophenoxy)but-1-ynyl]thiophen-2-yl}butan-1-ol,
1-1135: 2-amino-2-methyl-4-{5-[4-(4-fluorophenoxy)but-1-ynyl]thiophen-2-yl}butan-1-ol,
1-1136: 2-amino-2-methyl-4-{5-[4-(4-chlorophenoxy)but-1-ynyl]thiophen-2-yl}butan-1-ol,
1-1138: 2-amino-2-methyl-4-{5-[4-(3-methylphenoxy)but-1-ynyl]thiophen-2-yl}butan-1-ol,
1-1139: 2-amino-2-methyl-4-{5-[4-(4-methylphenoxy)but-1-ynyl]thiophen-2-yl}butan-1-ol,
1-1148: 2-amino-2-methyl-4-{5-[4-(3-trifluoromethylphenoxy)but-1-ynyl]thiophen-2-yl}butan-1-ol,
1-1149: 2-amino-2-methyl-4-{5-[4-(4-trifluoromethylphenoxy)but-1-ynyl]thiophen-2-yl}butan-1-ol,
1-1150: 2-amino-2-methyl-4-{5-[4-(3-methoxyphenoxy)but-1-ynyl]thiophen-2-yl}butan-1-ol,
1-1151: 2-amino-2-methyl-4-{5-[4-(4-methoxyphenoxy)but-1-ynyl]thiophen-2-yl}butan-1-ol,
1-1162: 2-amino-2-methyl-4-{5-[4-(3-methylthiophenoxy)but-1-ynyl]thiophen-2-yl}butan-1-ol,
1-1163: 2-amino-2-methyl-4-{5-[4-(4-methylthiophenoxy)but-1-ynyl]thiophen-2-yl}butan-1-ol,
1-1179: 2-amino-2-methyl-4-{5-[4-(3,4-dimethylphenoxy)but-1-ynyl]thiophen-2-yl}butan-1-ol,
1-1180: 2-amino-2-methyl-4-{5-[4-(3,4-dimethylphenoxy)but-1-ynyl]thiophen-2-yl}butan-1-ol,
1-1198; 2-amino-2-methyl-4-[5-(3-phenylmethoxypropynyl)thiophen-2-yl]butan-1-ol,
1-1202: 2-amino-2-methyl-4-{5-[3-(4-fluorophenyl)methoxypropynyl]thiophen-2-yl}butan-1-ol,
1-1203: 2-amino-2-methyl-4-{5-[3-(4-methylphenyl)methoxypropynyl]thiophen-2-yl}butan-1-ol,
1-1204: 2-amino-2-methyl-4-{5-[3-(4-ethylphenyl)methoxypropynyl]thiophen-2-yl}butan-1-ol,
1-1205: 2-amino-2-methyl-4-{5-[3-(4-trifluoromethylphenyl)methoxypropynyl]thiophen-2-yl}butan-1-ol,
1-1206: 2-amino-2-methyl-4-{5-[3-(4-methoxyphenyl)methoxyproynyl]thiophen-2-yl}butan-1-ol,
1-1207: 2-amino-2-methyl-4-{5-[3-(4-ethoxyphenyl)methoxypropynyl]thiophen-2-yl}butan-1-ol,
1-1208: 2-amino-2-methyl-4-{5-[3-(4-methylthiophenyl)methoxypropynyl]thiophen-2-yl}butan-1-ol,
1-1212: 2-amino-2-methyl-4-[5-(4-cyclohexyhmethoxybut-1-ynyl)thiophen-2-yl]butan-1-ol,
1-1266: 2-amino-2-methyl-4-[5-(4-phenylmethoxybut-1-ynyl)thiophen-2-yl]butan-1-ol,
1-1274: 2-amino-2-methyl-4-{5-[4-(3-fluorophenyl)methoxybut-1-ynyl]thiophen-2-yl}butan-1-ol,
1-1275: 2-amino-2-methyl-4-{5-[4-(4-fluorophenyl)methoxybut-1-ynyl]thiophen-2-yl}butan-1-ol,
1-1276: 2-amino-2-methyl-4-{5-[4-(4-chlorophenyl)methoxybut-1-ynyl]thiophen-2-yl}butan-1-ol,
1-1278: 2-amino-2-methyl-4-{5-[4-(3-methylphenyl)methoxybut-1-ynyl]thiophen-2-yl}butan-1-ol,
1-1279: 2-amino-2-methyl-4-{5-[4-(4-methylphenyl)methoxybut-1-ynyl]thiophen-2-yl}butan-1-ol,
1-1288: 2-amino-2-methyl-4-{5-[4-(3-tafluoromethylphenyl)methoxybut-1-ynyl]thiophen-2-yl}butan-1-ol,
1-1289: 2-amino-2-methyl-4-{5-[4-(4-trifluoromethylphenyl)methoxybut-1-ynyl]thiophen-2-yl}butan-1-ol,
1-1290: 2-amino-2-methyl-4-{5-[4-(3-methoxyphenyl)methoxybut-1-ynyl]thiophen-2-yl}butan-1-ol,
1-1291: 2-amino-2-methyl-4-{5-[4-(4-methoxyphenyl)methoxybut-1-ynyl]thiophen-2-yl}butan-1-ol,
1-1319: 2-amino-2-methyl-4-{5-[4-(3,4-dimethylphenyl)methoxybut-1-ynyl]thiophen-2-yl}butan-1-ol,
1-1320: 2-amino-2-methyl-4-{5-[4-(3,5-dimethylphenyl)methoxybut-1-ynyl]thiophen-2-yl}butan-1-ol,
1-1348: 2-amino-2-methyl-4-{5-[5-(4-fluorophenyl)pentanoyl]thiophen-2-yl}butan-1-ol,
1-1349: 2-amino-2-methyl-4-{5-[5-(4-methylphenyl)pentanoyl]thiophen-2-yl}butan-1-ol,
1-1350: 2-amino-2-methyl-4-{5-[5-(4-ethylphenyl)pentanoyl]thiophen-2-yl}butan-1-ol,
1-1351: 2-amino-2-methyl-4-{5-[5-(4-trifluorormethylphenyl)pentanoyl]thiophen-2-yl}butan-1-ol,
1-1352: 2-amino-2-methyl-4-{5-[5-(4-methoxyphenyl)pentanoyl]thiophen-2-yl}butan-1-ol,
1-1353: 2-amino-2-methyl-4-{5-[5-(4-ethoxyphenyl)pentanoyl]thiophen-2-yl}butan-1-ol,
1-1354: 2-amino-2-methyl-4-{5-[5-(4-methylthiophenyl)pentanoyl]thiophen-2-yl}butan-1-ol,
1-1476: 2-amino-2-methyl-4-{5-[4-(3-fluorophenoxy)butanoyl]thiophen-2-yl}butan-1-ol,
1-1477: 2-amino-2-methyl-4-{5-[4-(4-fluorophenoxy)butanoyl]thiophen-2-yl}butan-1-ol,
1-1478: 2-amino-2-methyl-4-{5-[4-(4-chlorophenoxy)butanoyl]thiophen-2-yl}butan-1-ol,
1-1480: 2-amino-2-methyl-4-{5-[4-(3-methylphenoxy)butanoyl]thiophen-2-yl}butan-1-ol,
1-1481: 2-amino-2-methyl-4-{5-[4-(4-methylphenoxy)butanoyl]thiophen-2-yl}butan-1-ol,
1-1490: 2-amino-2-methyl-4-{5-[4-(3-trifluoromethylphenoxy)butanoyl]thiophen-2-yl}butan-1-ol,
1-1491: 2-amino-2-methyl-4-{5-[4-(4-trifluoromethylphenoxy)butanoyl]thiophen-2-yl}butan-1-ol,
1-1492: 2-amino-2-methyl-4-{5-[4-(3-methoxyphenoxy)butanoyl]thiophen-2-yl}butan-1-ol,
1-1493: 2-amino-2-methyl-4-{5-[4-(4-methoxyphenoxy)butanoyl]thiophen-2-yl}butan-1-ol,
1-1504: 2-amino-2-methyl-4-{5-[4-(3-methylthiophenyl)butanoyl]thiophen-2-yl}butan-1-ol,
1-1505: 2-amino-2-methyl-4-{5-[4-(4-methylthiophenoxy)butanoyl]thiophen-2-yl}butan-1-ol,
1-1521: 2-amino-2-methyl-4-{5-[4-(3,4-dimethylphenoxy)butanoyl]thiophen-2-yl}butan-1-ol,
1-1522: 2-amino-2-methyl-4-{5-[4-(3,5-dimethylphenoxy)butanoyl]thiophen-2-yl}butan-1-ol,
1-2093: 2-amino-2-ethyl-4-[5-(4-phenylbutanoyl)thiophen-2-yl]butan-1-ol,
1-2101: 2-amino-2-ethyl-4-[5-(5-phenylpentanoyl)thiophen-2-yl]butan-1-ol,
1-2109: 2-amino-2-ethyl-4-[5-(4-phenylhexanoyl)thiophen-2-yl]butan-1-ol,
1-2257: 2-amino-2-methyl-4-{5-[5-(3,4-difluorophenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol,
1-2258: 2-amino-2-methyl-4-{5-[5-(3,4-difluorophenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol,
1-2259: 2-amino-2-methyl-4-{5-[5-(3-chlorophenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol,
1-2260: 2-amino-2-methyl-4-{5-[5-(3,4-dichlorophenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol,
1-2261: 2-amino-2-methyl-4-{5-[5-(3,4-dichlorophenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol,
1-2262: 2-amino-2-methyl-4-{5-[5-(3,4-ditrifluoromethylphenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol,
1-2263: 2-amino-2-methyl-4-{5-[5-(3,5-ditrifluoromethylphenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol,
1-2264: 2-amino-2-methyl-4-{5-[5-(3,4-dimethoxyphenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol,
1-2265: 2-amino-2-methyl-4-{5-[5-(3,5-dimethoxyphenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol,
1-2266: 2-amino-2-methyl-4-{5-[5-(3,4,5-trimethoxyphenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol,
1-2267: 2-amino-2-methyl-4-{5-[5-(3-acetylphenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol,
1-2268: 2-amino-2-methyl-4-{5-[5-(4-acetylphenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol,
1-2269: 2-amino-2-methyl-4-{5-[5-(3-fluorophenoxy)propynyl]thiophen-2-yl}butan-1-ol,
1-2270: 2-amino-2-methyl-4-{5-[3-(3,4-difluorophenoxy)propynyl]thiophen-2-yl}butan-1-ol,
1-2271: 2-amino-2-methyl-4-{5-[3-(3,5-difluorophenoxy)propynyl]thiophen-2-yl}butan-1-ol,
1-2272: 2-amino-2-methyl-4-{5-[3-(3-chlorophenoxy)propynyl]thiophen-2-yl}butan-1-ol,
1-2273: 2-amino-2-methyl-4-{5-[3-(4-chlorophenoxy)propynyl]thiophen-2-yl}butan-1-ol,
1-2274: 2-amino-2-methyl-4-{5-[3-(3,4-dichlorophenoxy)propynyl]thiophen-2-yl}butan-1-ol,
1-2275: 2-amino-2-methyl-4-{5-[3-(3,5-dichlorophenoxy)propynyl]thiophen-2-yl}butan-1-ol,
1-2276: 2-amino-2-methyl-4-{5-[3-(3-methylphenoxy)propynyl]thiophen-2-yl}butan-1-ol,
1-2278: 2-amino-2-methyl-4-{5-[3-(3,4-dimethylphenoxy)propynyl]thiophen-2-yl}butan-1-ol,
1-2279: 2-amino-2-methyl-4-{5-[3-(3,5-dimethylphenoxy)propynyl]thiophen-2-yl}butan-1-ol,
1-2280: 2-amino-2-methyl-4-{5-[3-(3-trifluoromethylphenoxy)propynyl]thiophen-2-yl}butan-1-ol,
1-2281: 2-amino-2-methyl-4-{5-[3-(3,4-difluoromethylphenoxy)propynyl]thiophen-2-yl}butan-1-ol,
1-2282: 2-amino-2-methyl-4-{5-[3-(3,5-ditrifluoromethylphenoxy)propynyl]thiophen-2-yl}butan-1-ol,
1-2283: 2-amino-2-methyl-4-{5-[3-(3-methoxyphenoxy)propynyl]thiophen-2-yl}butan-1-ol,
1-2284: 2-amino-2-methyl-4-{5-[3-(3,4-dimethoxyphenyl)propynyl]thiophen-2-yl}butan-1-ol,
1-2285: 2-amino-2-methyl-4-{5-[3-(3,5-ethoxyphenoxy)propynyl]thiophen-2-yl}butan-1-ol,
1-2286: 2-amino-2-methyl-4-{5-[3-(3,4,5-trimethoxyphenoxy)propynyl]thiophen-2-yl}butan-1-ol,
1-2287: 2-amino-2-methyl-4-{5-[3-(3-acetylphenoxy)propynyl]thiophen-2-yl}butan-1-ol,
1-2288: 2-amino-2-methyl-4-{5-[3-(4-acetylphenoxy)propynyl]thiophen-2-yl}butan-1-ol,
1-2290: 2-amino-2-methyl-4-{5-[4-(3,4-difluorophenoxy)but-1-ynyl]thiophen-2-yl}butan-1-ol,
1-2291: 2-amino-2-methyl-4-{5-[4-(3,5-difluorophenoxy)but-1-ynyl]thiophen-2-yl}butan-1-ol,
1-2292: 2-amino-2-methyl-4-{5-[4-(3-chlorophenoxy)but-1-ynyl]thiophen-2-yl}butan-1-ol,
1-2293: 2-amino-2-methyl-4-{5-[4-(3,4-dichlorophenoxy)but-1-ynyl]thiophen-2-yl}butan-1-ol,
1-2294: 2-amino-2-methyl-4-{5-[4-(3,5-dichlorophenoxy)but-1-ynyl]thiophen-2-yl}butan-1-ol,
1-2295: 2-amino-2-methyl-4-{5-[4-(3,4-ditrifluoromethylphenoxy)but-1-ynyl]thiophen-2-yl}butan-1-ol,
1-2296: 2-amino-2-methyl-4-{5-[4-(3,5-ditrifluoromethylphenoxy)but-1-ynyl]thiophen-2-yl}butan-1-ol,
1-2297: 2-amino-2-methyl-4-{5-[4-(3,4-dimethoxyphenoxyl)but-1-ynyl]thiophen-2-yl}butan-1-ol,
1-2298: 2-amino-2-methyl-4-{5-[4-(3,5-dimethoxyphenoxy)but-1-ynyl]thiophen-2-yl}butan-1-ol,
1-2299: 2-amino-2-methyl-4-{5-[4-(3,4,5-trimethoxyphenoxy)but-1-ynyl]thiophen-2-yl}butan-1-ol,
1-2300: 2-amino-2-methyl-4-{5-[4-(3-acetylphenoxy)but-1-ynyl]thiophen-2-yl}butan-1-ol,
1-2301: 2-amino-2-methyl-4-{5-[4-(4-acetylphenoxy)but-1-ynyl]thiophen-2-yl}butan-1-ol,
1-2328: 2-amino-2-methyl-4-{5-[5-(3-fluorophenyl)pentanoyl]thiophen-2-yl}butan-1-ol,
1-2329: 2-amino-2-methyl-4-{5-[5-(3,4-difluorophenyl)pentanoyl]thiophen-2-yl}butan-1-ol,
1-2330: 2-amino-2-methyl-4-{5-[5-(3,5-difluorophenyl)pentanoyl]thiophen-2-yl}butan-1-ol,
1-2331: 2-amino-2-methyl-4-{5-[5-(3-chlorophenyl)pentanoyl]thiophen-2-yl}butan-1-ol,
1-2332: 2-amino-2-methyl-4-{5-[5-(4-chlorophenyl)pentanoyl]thiophen-2-yl}butan-1-ol,
1-2333: 2-amino-2-methyl-4-{5-[5-(3,4-dichlorophenyl)pentanoyl]thiophen-2-yl}butan-1-ol,
1-2334: 2-amino-2-methyl-4-{5-[5-(3,5-dichlorophenyl)pentanoyl]thiophen-2-yl}butan-1-ol
1-2335: 2-amino-2-methyl-4-{5-[5-(3-methylphenyl)pentanoyl]thiophen-2-yl}butan-1-ol,
1-2336: 2-amino-2-methyl-4-{5-[5-(3,4-dimethylphenyl)pentanoyl]thiophen-2-yl}butan-1-ol,
1-2337: 2-amino-2-methyl-4-{5-[5-(3,4-dimethylphenyl)pentanoyl]thiophen-2-yl}butan-1-ol,
1-2338: 2-amino-2-methyl-4-{5-[5-(3-trifluoromethylphenyl)pentanoyl]thiophen-2-yl}butan-1-ol,
1-2339: 2-amino-2-methyl-4-{5-[5-(3,4-ditrifluoromethylphenyl)pentanoyl]thiophen-2-yl}butan-1-ol,
1-2340: 2-amino-2-methyl-4-{5-[5-(3,5-ditrifluoromethylphenyl)pentanoyl]thiophen-2-yl}butan-1-ol,
1-2341: 2-amino-2-methyl-4-{5-[5-(3-methoxyphenyl)pentanoyl]thiophen-2-yl}butan-1-ol,
1-2342: 2-amino-2-methyl-4-{5-[5-(3,4-dimethoxyphenyl)pentanoyl]thiophen-2-yl}butan-1-ol,
1-2343: 2-amino-2-methyl-4-{5-[5-(3,5-dimethoxyphenyl)pentanoyl]thiophen-2-yl}butan-1-ol,
1-2344: 2-amino-2-methyl-4-{5-[5-(3,4,5-trimethoxyphenyl)pentanoyl]thiophen-2-yl}butan-1-ol,
1-2345: 2-amino-2-methyl-4-{5-[5-(3-acetylphenyl)pentanoyl]thiophen-2-yl}butan-1-ol, and
1-2346: 2-amino-2-methyl-4-{5-[5-(4-acetylphenyl)pentanoyl]thiophen-2-yl}butan-1-ol.
Most preferred compounds are those of Exemplification compounds numbers:
1-71: 2-amino-2-methyl-4-[5-(4-cyclohexylbutyl)thiophen-2-yl]butan-1-ol,
1-98: 2-amino-2-methyl-4-[5-(5-cyclohexylpentyl)thiophen-2-yl]butan-1-ol,
1-152: 2-amino-2-methyl-4-[5-(5-phenylpentyl)thiophen-2-yl]butan-1-ol,
1-400: 2-amino-2-methyl-4-[5-(4-cyclohexyloxybutyl)thiophen-2-yl]butan-1-ol,
1-463: 2-amino-2-methyl-4-{5-[4-(4-fluorophenoxy)butyl]thiophen-2-yl)butan-1-ol,
1-479: 2-amino-2-methyl-1-{5-[4-(4-methoxyphenoxy)butyl]thiophen-2-yl}butan-1-ol,
1-594: 2-amino-2-methyl-4-[5-(4-benzyloxybutyl)thiophen-2-yl]butan-1-ol,
1-743: 2-amino-2-methyl-4-[5-(4-cyclohexylbut-1-ynyl)thiophen-2-yl]butan-1-ol,
1-756: 2-amino-2-methyl-4-[5-(4-phenylbut-1-ynyl)thiophen-2-yl]butan-1-ol,
1-770: 2-amino-2-methyl-4-[5-(5-cyclohexylpent-1-ynyl)thiophen-2-yl]butan-1-ol,
1-824: 2-amino-2-methyl-4-[5-(5-phenylpent-1-ynyl)thiophen-2-yl]butan-1-ol,
1-833: 2-amino-2-methyl-4-{5-[5-(4-fluorophenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol,
1-849: 2-amino-2-methyl-4-{5-[5-(4-methoxyphenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol,
1-1050: 2-amino-2-methyl-4-{5-[3-(4-methylcyclohexyloxy)propynyl]thiophen-2-yl}butan-1-ol,
1-1063: 2-amino-2-methyl-4-{5-[5-(4-methylphenoxy)propynyl]thiophen-2-yl}butan-1-ol,
1-1064: 2-amino-2-methyl-4-{5-[3-(4-ethylphenoxy)propynyl]thiophen-2-yl}butan-1-ol,
1-1068: 2-amino-2-methyl-4-{5-[3-(4-methylthiophenoxy)propynyl]thiophen-2-yl}butan-1-ol,
1-1072: 2-amino-2-methyl-4-[5-(4-cyclohexyloxybut-1-ynyl)thiophen-2-yl]butan-1-ol,
1-1135: 2-amino-2-methyl-4-{5-[4-(4-fluorophenoxy)but-1-ynyl]thiophen-2-yl}butan-1-ol,
1-1139: 2-amino-2-methyl-4-{5-[4-(4-methylphenoxy)but-1-ynyl]thiophen-2-yl}butan-1-ol,
1-1185: 2-amino-2-methyl-4-[5-(3-cyclohexylmethoxypropynyl)thiophen-2-yl}butan-1-ol,
1-1266: 2-amino-2-methyl-4-[5-(4-phenylmethoxybut-1-ynyl)thiophen-2-yl]butan-1-ol,
1-1329: 2-amino-2-methyl-4-[5-(4-cyclohexylbutanoyl)thiophen-2-yl]butan-1-ol,
1-1330: 2-amino-2-methyl-4-[5-(4-phenylbutanoyl)thiophen-2-yl]butan-1-ol,
1-1331: 2-amino-2-methyl-4-[5-(5-cyclohexylpentanoyl)thiophen-2-yl]butan-1-ol,
1-1344: 2-amino-2-methyl-4-[5-(5-phenylpentanoyl)thiophen-2-yl]butan-1-ol,
1-1348: 2-amino-2-methyl-4-{5-[5-(4-fluorophenyl)pentanoyl]thiophen-2-yl}butan-1-ol,
1-1764: 2-amino-2-ethyl-4-[5-(5-cyclohexylpentyl)thiophen-2-yl]butan-1-ol,
1-1909: 2-amino-2-ethyl-4-[5-(5-cyclohexylpent-1-ynyl)thiophen-2-yl]butan-1-ol,
1-2097: 2-amino-2-ethyl-4-[5-(5-cyclhexylpentanoyl)thiophen-2-yl]butan-1-ol,
1-2273: 2-amino-2-methyl-4-{5-[3-(4-chlorophenoxy)propynyl]thiophen-2-yl}butan-1-ol,
1-2276: 2-amino-2-methyl-4-{5-[3-(3-methylphenoxy)propynyl]thiophen-2-yl}butan-1-ol,
1-2278: 2-amino-2-methyl-4-{5-[3-(3,4-dimethylphenoxy)propynyl]thiophen-2-yl}butan-1-ol,
1-2283: 2-amino-2-methyl-4-{5-[3-(3-methoxyphenoxy)propynyl]thiophen-2-yl}butan-1-ol,
1-2284: 2-amino-2-methyl-4-{5-[3-(3,4-dimethoxyphenyl)propynyl]thiophen-2-yl}butan-1-ol,
1-2285: 2-amino-2-methyl-4-{5-[3-(3,5-dimethoxyphenoxy)propynyl]thiophen-2-yl}butan-1-ol,
1-2287: 2-amino-2-methyl-4-{5-[3-(3-acetylphenoxy)propynyl]thiophen-2-yl}butan-1-ol, and
1-2288: 2-amino-2-methyl-4-{5-[3-(4-acetylphenoxy)propynyl]thiophen-2-yl}butan-1-ol.
Prefer compounds in Table 3 and 4 are those of Exemplification compounds numbers 3-5, 3-6, 3-7, 3-8, 3-11, 3-12, 4-4, 4-5, 4-6, 4-7, 4-8, 4-9, 4-10, 4-11, 4-12, 4-13, 4-17, 4-23, 4-24, 4-27, 4-28, 4-3 1, and 4-32.
Most preferred compounds are those Exemplification compounds numbers:
4-4: 4-methyl-4-[(thiophen-3-yl)ethyl]oxazolidinone,
4-5: 4-methyl-4-[(thiophen-3-yl)ethyl]oxazolidinone,
4-8: 4-methyl-4-[(5-bromothiophen-3-yl)ethyl]oxazolidinone, and
4-9: 4-methyl-4-[(5-bromothiophen-3-yl)ethyl]oxazolidinone.
Compounds of formulae (I), (XLIVa), (XLIVb), (La) and (Lb) can be prepared according to the methods described below.
In method A, a compound (I) and a compound (Ic) (which is a compound (I) where R1 is a hydrogen atom and R2 is a lower alkoxycarbonyl group, an aralkyloxycarbonyl group or an aralkyloxycarbonyl group substituted by 1-3 substituents selected from the substituent group a) are synthesized. 
In the above scheme, R1, R2, R3, R4, R5, R6, R7, X, Y and n are as defined earlier; R8 is a formyl group, a carboxyl group or a lower alkoxycarbonyl group; R9 and R9a are the same or different and each is independently a hydrogen atom or a lower alkyl group; R10 is a lower alkyl group, an aralkyl group or an aralkyl group substituted by 1-3 substituents selected from the substituent group a; and R5a, R6a and R7a are an amino group, a hydroxyl group and/or a carboxyl group, each of which is contained as the substituent in each definition of R5, R6 and R7 and optionally protected by a suitable protecting group, in addition to the same groups as those defined earlier for R5, R6 and R7.
In the above description, the xe2x80x9cprotecting groupxe2x80x9d of the xe2x80x9camino group optionally protectedxe2x80x9d in the definition of R5a, R6a and R7a is not particularly limited provided that it is a protecting group of an amino group used in the field of the organic synthetic chemistry and is the same as that defined earlier. A lower alkoxycarbonyl group is preferred and a t-butoxycarbonyl group is most preferred.
In the above description, the xe2x80x9cprotecting groupxe2x80x9d of the xe2x80x9chydroxyl group optionally protectedxe2x80x9d in the definition of R5a, R6a and R7a is not particularly limited provided that it is a protecting group of a hydroxyl group used in the field of the organic synthetic chemistry. This protecting group is, for example, the same as that defined earlier as the xe2x80x9ccommon protecting group used for the protection of a hydroxyl group by esterificationxe2x80x9d, and the preferable examples include a lower aliphatic acyl group, an aromatic acyl group, a lower alkoxycarbonyl group or a (lower alkoxy)methyl group, and form preferable examples are a lower aliphatic acyl group or a (lower alkoxycarbonyl)methyl group. The most preferable example is an acetyl group or a methoxymethyl group.
In the above description, the xe2x80x9cprotecting groupxe2x80x9d of the xe2x80x9ccarboxyl group optionally protectedxe2x80x9d in the definition of R5a, R6a and R7a is not particularly limited provided that it is a protecting group of a carboxyl group used in the field of the organic synthetic chemistry. This protecting group is, for example, the same as that defined earlier as the xe2x80x9ccommon protecting groups used for the protection of a carboxyl group by esterificationxe2x80x9d, and the preferable examples include a lower alkyl group, and a methyl group is most preferable.
In Step A1, a compound of general formula (III) is prepared by the reaction of a compound of general formula (II) with a reducing agent in an inert solvent in the presence or absence of a base (preferably in the presence of a base).
The inert solvent used in the above-mentioned reaction is not particularly limited provided that it has no adverse effect on the reaction and dissolves the starting materials to some extent.
Examples of suitable solvents include aliphatic hydrocarbons such as hexane, heptane, ligmin or petroleum ether, aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as chloroform, methylene chloride, 1,2-dichloroethane or carbon tetrachloride; esters such as acetic acid, methyl acetate, ethyl acetate, propyl acetate, butyl acetate or diethyl carbonate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or di(ethylene glycol)dimethyl ether; alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerol, octanol, cyclohexanol or methyl cellosolve; amides such as formamide, dimethylformamide, dimethylacetamide or hex amethylphosphoric triamide; water; or mixtures of water and solvents thereof or of solvents thereof. Of these solvents, ethers are preferred and tetrahydrofuran is most preferred.
The reducing agent used in the above-mentioned reaction is, for example, an alkali metal borohydride such as sodium borohydride, lithium borohydride or sodium cyanoborohydride; or an aluminium hydride derivative such as diisobutylaluminium hydride, lithium aluminium hydride or triethoxyaluminium lithium hydride. The preferred examples are alkali metal borohydrides, and sodium borohydride is most preferred.
The reaction temperature mainly depends on the starting material compounds, the reducing agent and the solvent employed in the reaction. The reaction is usually carried out at a temperature of from xe2x88x9250xc2x0 C. to 100xc2x0 C. (preferably from 0xc2x0 C. to 50xc2x0 C.).
The reaction time mainly depends on the stating material compounds, the reducing agent, the solvent and the reaction temperature employed in the reaction. The reaction is usually carried out in a period of from 15 minutes to 150 hours (preferably from 1 hour to 100 hours).
After the completion of the reaction, the target compounds (III) of this reaction may be collected from the reaction mixture according to conventional methods. For example, the target compound can be obtained by conducting the following steps successively: appropriately neutralizing the reaction mixture; removing, if any, insoluble material(s) by filtration; adding an organic solvent which is not miscible with water (e.g. ethyl acetate); separating the organic layer containing the target compound; washing the extract with, for example, water and then drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate or the like; and removing solvent by evaporation. The target compound can be isolated and purified, if necessary, by a suitable combination of the conventional methods commonly used for the separation/purification of organic compounds such as recrystallization, reprecipitation and chromatography using appropriate eluent(s).
In Step A2, a compound of general formula (IV) is prepared by converting a hydroxyl group in the compound of formula (III) into a leaving group in an inert solvent in the presence of a base and then by iodination reaction of the resulting leaving group with an iodination agent
The reagent used for the formation of the leaving group is, for example, a halogenation agent including sulfonyl halides such as methanesulfonyl chloride or p-toluenesulfonyl chloride; thionyl halides such as thionyl chloride, thionyl bromide or thionyl iodide; sulfuryl halides such as sulfuryl chloride, sulfuryl bromide or sulfuryl iodide; phosphorus trihalogenides such as phosphorus trichloride, phosphorus tribromide or phosphorus triiodide; phosphorus pentahalogenides such as phosphorus pentachloride, phosphorus pentabromide or phosphorus pentaiodide; phosphorus oxyhalogendes such as phosphorus oxychloride, phosphorus oxybromide or phosphorus oxyiodide; or rhenium reagents such as methyltrioxophenium (VII). Of these reagents, sulfonyl halides are preferred.
Examples of bases which can be used in the conversion of the hydroxyl group into the leaving group include alkali metal carbonates such as lithium carbonate, sodium carbonate or potassium carbonate; alkali metal bicarbonates such as lithium bicarbonate, sodium bicarbonate or potassium bicarbonate; alkali metal hydrides such as lithium hydride, sodium hydride or potassium hydride; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide or potassium hydroxide; alkali metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide or potassium t-butoxide; and organic amines such as triethylamine, tributyl amine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine, N,N-dimethylaniline, N,N-diethylaniline, 1,5-diazabicyclo[4.3.0]nona-5-ene, 1,4-diazabicyclo[2.2.2]octane (DABCO) or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The organic amines (particularly triethylamine) are preferable.
The inert solvent which can be used in the conversion of the hydroxyl group into the leaving group is not particularly limited provided that it has no adverse effect on the reaction. Examples of suitable solvents include aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as chloroform, methylene chloride, 1,2-dichloroethane or carbon tetrachloride; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or di(ethylene glycol)dimethyl ether, ketones such as acetone or 2-butanone; amides such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; sulfoxides such as dimethyl sulfoxide; or sulfolane. Of these solvents, halogenated hydrocarbons are preferred and methylene chloride is most preferred.
The reaction temperature in the case of the conversion of the hydroxyl group into the leaving group mainly depends on the starting material compounds, the reagent and the solvent employed in the reaction. The reaction is usually carried out at a temperature of from xe2x88x9250xc2x0 C. to 200xc2x0 C. preferably from xe2x88x9210xc2x0 C. to 150xc2x0 C.).
The reaction time in the case of the conversion of the hydroxyl group into the leaving group mainly depends on the starting material compounds, the reagent, the solvent and the reaction temperature employed in the reaction. The reaction is usually carried out in a period of from 15 minutes to 24 hours (preferably from 30 minutes to 12 hours).
The iodination agent that can be used in the above-mentioned reaction is, for example, phosphorus pentaiodide, phosphorus oxyiodide, sodium iodide or potassium iodide, and sodium iodide is preferred.
The reaction temperature in the case of the iodination of the leaving group mainly depends on the starting material compounds, the reagent and the solvent employed in the reaction. The reaction is usually carried out at a temperature of from 0xc2x0 C. to 200xc2x0 C. (preferably from 10xc2x0 C. to 150xc2x0 C.).
The reaction time in the case of the iodination of the leaving group mainly depends on the starting material compounds, the reagent, the solvent and the reaction temperature employed in the reaction. The reaction is usually carried out in a period of from 15 minutes to 24 hrs (preferably from 30 minutes to 12 hours).
After the completion of the reaction, the target compounds (IV) of this reaction may be collected from the reaction mixture according to conventional methods. For example, the target compound can be obtained by conducting the following steps successively: appropriately neutralizing the reaction mixture; removing, if any, insoluble material(s) by filtration; adding an organic solvent which is not miscible with water (e.g. ethyl acetate); separating the organic layer containing the target compound; washing the extract with, for example, water and then drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhlydrous sodium bicarbonate or the like; and removing solvent by evaporation. The target compound can be isolated and purified, if necessary, by a suitable combination of the conventional methods commonly used for the separation/purification of organic compounds such as recrystallization, reprecipitation and chromatography using appropriate eluent(s).
In Step A3, a compound of general formula (VI) is prepared by the reaction of a compound (IV) with a compound of general formula (V) in an inert solvent in the presence of a base.
The inert solvent used in the above-mentioned reaction is not particularly limited provided that it has no adverse effect on the reaction. Examples of suitable solvents include ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or di(ethylene glycol)dimethyl ether, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerol, octanol, cyclohexanol or methyl cellosolve; amides such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoric tramide; water; or mixtures of water and solvents thereof or of solvents thereof. Of these solvents, alcohols or amides are preferred and dimethylformamide is most preferred.
The base used in the above-mentioned reaction is, for example, the same as that used for the conversion of the hydroxyl group into the leaving group described in Step A2 of the method A, and alkali metal hydrides or alkali metal alkoxides (most preferably sodium hydride) are preferred.
The reaction temperature mainly depends on the starting material compounds, the base and the solvent employed in the reaction. The reaction is usually carried out at a temperature of from xe2x88x9278xc2x0 C. to 100xc2x0 C. (preferably from 0xc2x0 C. to 50xc2x0 C.).
The reaction time mainly depends on the starting material compounds, the base, the solvent and the reaction temperature employed in the reaction. The reaction is usually carried out in a period of from 15 minutes to 48 hours (preferably from 30 minutes to 12 hours).
After the completion of the reaction, the target compounds (VI) of this reaction may be collected from the reaction mixture according to conventional methods. For example, the target compound can be obtained by conducting the following steps successively: appropriately neutralizing the reaction mixture; removing, if any, insoluble material(s) by filtration; adding an organic solvent which is not miscible with water (e.g. ethyl acetate); separating the organic layer containing the target compound; washing the extract with, for example, water and then drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate or the like; and removing solvent by evaporation. The target compound can be isolated and purified, if necessary, by a suitable combination of the conventional methods commonly used for the separation/purification of organic compounds such as recrystallization, reprecipitation and chromatography using appropriate eluent(s).
In Step A4, a compound of general formula (VII) is prepared by converting an ester group of a compound (VI) into a carboxyl group by a hydrolysis reaction with a base.
The inert solvent used in the above-mentioned reaction is not particularly limited provided that it has no adverse effect on the reaction. Examples of suitable solvents include aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; others such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or di(ethylene glycol)dimethyl ether; alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerol, octanol, cyclohexanol or methyl cellosolve; water; or mixtures of water and solvents thereof or of solvents thereof. Of these solvents, alcohols (particularly ethanol) are preferred.
The base used in the above-mentioned reaction is, for example, the same as that used for the conversion of a hydroxyl group into a leaving group described in Step A2 of the method A, and alkali metal hydroxides (most preferably potassium hydroxide) are preferred.
The reaction temperature mainly depends on the starting material compounds, the base and the solvent employed in the reaction. The reaction is usually carried out at a temperature of from xe2x88x9220xc2x0 C. to 200xc2x0 C. (preferably from 0xc2x0 C. to 50xc2x0 C.).
The reaction time mainly depends on the starting material compounds, the base, the solvent and the reaction temperature employed in the reaction. The reaction is usually carried out in a period of from 30 minutes to 120 hours preferably from 1 hour to 80 hours).
After the completion of the reaction, the compound (VII) prepared as the target compound in this reaction may be collected from the reaction mixture according to a conventional method.
For example, the target compound can be obtained by conducting the following steps successively: appropriately neutralizing the reaction mixture; removing, if any, insoluble material(s) by filtration; adding an organic solvent which is not miscible with water (e.g. ethyl acetate); separating the organic layer containing the target compound; washing the extract with, for example, water and then drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate or the like; and removing solvent by evaporation. The target compound can be isolated and purified, if necessary, by a suitable combination of the conventional methods commonly used for the separation/purification of organic compounds such as recrystallization, reprecipitation and chromatography using appropriate eluent(s).
Step A5 is a step for converting a carboxyl group into a carbamoyl group by the Curtius Rearrangement Reaction, and in this step, a compound of general formula (IX) is synthesized by the reaction of a compound (VII) with a diarylphosphoryl azide derivative such as diphenylphosphoryl azide in an inert solvent in the presence of a base and then by heating the resulting product with a compound of general formula (VII).
The inert solvent used in the above-mentioned reaction is not particularly limited provided that it has no adverse effect on the reaction. Examples of suitable solvents include aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether, aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as chloroform, methylene chloride, 1,2-dichloroethane or carbon tetrachloride; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or di(ethylene glycol)dimethyl ether, water, or mixtures of water and solvents thereof or of solvents thereof. Of these solvents, aromatic hydrocarbons (particularly benzene) are preferred.
The base used in the above-mentioned reaction is, for example, the same as that used for the conversion of a hydroxyl group into a leaving group described in Step A2 of the method A, and organic amines (most preferably triethylamine) are preferred.
The reaction temperature for the reactions of the compound (VII) with diarylphophoryl azide derivative and of the resulting product with the compound (VIII) mainly depends on the starting material compounds, the base and the solvent employed in the reaction. The reaction is usually carried out at a temperature of from 0xc2x0 C. to 200xc2x0 C. (preferably from 20xc2x0 C. to 150xc2x0 C.).
The reaction time for the reactions of the compound (VII) with diarylphophoryl azide derivative and of the resulting product with the compound (VIII) mainly depends on the starting material compounds, the base, the solvent and the reaction temperature employed in the reaction. The reaction is usually carried out in a period of from 15 minutes to 24 hours (preferably from 30 minutes to 12 hours).
In addition, even in the case where a compound (VIII) which is difficult to react directly with a diarylphophoryl azide derivative is used, the carboxyl group of the compound (VI) can be converted into the carbamoyl group without any problem by the reaction mentioned above.
After the completion of the reaction, the compound (IX) prepared as the target compound in this reaction may be collected from the reaction mixture according to a conventional method. For example, the target compound can be obtained by conducting the following steps successively: appropriately neutralizing the reaction mixture; removing, if any, insoluble material(s) by filtration; adding an organic solvent which is not miscible with water (e.g. ethyl acetate); separating the organic layer containing the target compound; washing the extract with, for example, water and then drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate or the like; and removing solvent by evaporation. The target compound can be isolated and purified, if necessary, by a suitable combination of the conventional methods commonly used for the separation/purification of organic compounds such as recrystallization, reprecipitation and chromatography using appropriate eluent(s).
In Step A6, a compound of general formula (X) is prepared by reducing an ester group of a compound (IX) with a reducing agent in an inert solvent.
The inert solvent used in the above-mentioned reaction is not particularly limited provided that it has no adverse effect on the reaction. Examples of suitable solvents include aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether, aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as chloroform, methylene chloride, 1,2-dichloroethane or carbon tetrachloride; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or di(ethylene glycol)dimethyl ether, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerol, octanol, cyclobexanol or methyl cellosolve; or mixtures of solvents thereof. Of these solvents, mixtures of alcohols and ethers (particularly a mixture of ethanol and tetrahydrofuran) are preferred.
The reducing agent used in the above-mentioned reaction is, for example, the same as that used in Step A1 of the method A, and alkali metal borohydrides (most preferably sodium borohydride or lithium borohydride) are preferred.
The reaction temperature mainly depends on the starting material compounds and the solvent employed in the reaction. The reaction is usually carried out at a temperature of from xe2x88x9278xc2x0 C. to 150xc2x0 C. (preferably from xe2x88x9220xc2x0 C. to 50xc2x0 C.).
The reaction time mainly depends on the starting material compounds, the solvent and the reaction temperature employed in the reaction. The reaction is usually carried out in a period of from 5 minutes to 48 hours (preferably from 30 minutes to 24 hours).
After the completion of the reaction, the compound (X) prepared as the target compound in this reaction may be collected from the reaction mixture according to a conventional method. For example, the target compound can be obtained by conducting following the steps successively: appropriately neutralizing the reaction mixture; removing, if any, insoluble material(s) by filtration; adding an organic solvent which is not miscible with water (e.g. ethyl acetate); separating the organic layer containing the target compound; washing the extract with, for example, water and then drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate or the like; and removing solvent by evaporation. The target compound can be isolated and purified, if necessary, by a suitable combination of the conventional methods commonly used for the separation/purification of organic compounds such as recrystallization, reprecipitation and chromatography using appropriate eluent(s).
In Step A7, a compound of general formula (XI) having an oxazolidine ring is prepared by the reaction of a compound (X) with a base.
The inert solvent used in the above-mentioned reaction is not particularly limited provided that it has no adverse effect on the reaction. Examples of suitable solvents include ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or di(ethylene glycol)dimethyl ether; alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerol, octanol, cyclohexanol or methyl cellosolve; amides such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; water; or mixtures of water and solvents thereof or of solvents thereof. Of these solvents, alcohols or amides (particularly dimethylformamide) are preferred.
The base used in the above-mentioned reaction is, for example, the same as that used for the conversion of the hydroxyl group into the leaving group described in Step A2 of the method A, and alkali metal alkoxides (most preferably potassium t-butoxide) are preferred.
The reaction temperature mainly depends on the starting material compounds, the base and the solvent employed in the reaction. The reaction is usually carried out at a temperature of from xe2x88x9278xc2x0 C. to 100xc2x0 C. (preferably from xe2x88x9250xc2x0 C. to 50xc2x0 C.).
The reaction time mainly depends on the starting material compounds, the base, the solvent and the reaction temperature employed in the reaction. The reaction is usually carried out in a period of from 15 minutes to 48 hours (preferably from 30 minutes to 12 hours).
After the completion of the reaction, the compound (XI) prepared as the target compound in this reaction may be collected from the reaction mixture according to a conventional method.
For example, the target compound can be obtained by conducting the following steps successively; appropriately neutralizing the reaction mixture; removing, if any, insoluble material(s) by filtration; adding an organic solvent which is not miscible with water (e.g. ethyl acetate); separating the organic layer containing the target compound; washing the extract with, for example, water and then drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate or the like; and removing solvent by evaporation. The target compound can be isolated and purified, if necessary, by a suitable combination of conventional methods commonly used for the separation/purification of organic compounds such as recrysallization, reprecipitation and chromatography using appropriate eluent(s).
In Step A8, a compound of general formula (I) is prepared by hydrolyzing a compound (XI) with a base in an inert solvent and then, if necessary, by conducting successively the removal of an amino-, a hydroxyl- and/or a carboxyl-protecting group in R1, R2, R3, R5a, R6a and R7a, and the protection of an amino group in R1 and/or R2, and/or a protection of a hydroxyl group in R3.
The inert solvent used in the reaction of the compound (XI) with the base is not particularly limited provided that it has no adverse effect on the reaction. Examples of suitable solvents include aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether, aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as chloroform, methylene chloride, 1,2-chloroethane or carbon tetrachloride; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or di(ethylene glycol)dimethyl ether, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol isoamyl alcohol, diethylene glycol, glycerol, octanol, cyclohexanol or methyl cellosolve; water, or mixtures of solvents thereof. Of these solvents, mixtures of alcohols and ethers (particularly mixture of methanol and tetrahydrofuran) are preferred.
The base used in the reaction of the compound (XI) with the base is, for example, the same as that used for the conversion of a hydroxyl group into a leaving group described in Step A2 of the method A, and alkali metal hydroxides (most preferably potassium hydroxide) are preferred.
The reaction temperature mainly depends on the starting material compounds, the base and the solvent employed in the reaction. The reaction is usually carried out at a temperature of from xe2x88x9220xc2x0 C. to 200xc2x0 C. (preferably from 0xc2x0 C. to 100xc2x0 C.).
The reaction time mainly depends on the starting material compounds, the base, the solvent and the reaction temperature employed in the reaction. The reaction is usually carried out in a period of from 30 minutes to 48 hours (preferably from 1 hour to 24 hours).
The procedures for removing the amino- and the hydroxyl-protecting groups depend on the nature of the protecting group used, but the removal of the protecting group is generally carried out according to the known procedures commonly used in organic synthetic chemistry. This deprotection reaction is, for example, performed by the procedures described in the literature (T. W. Green: Protective Groups in Organic Synthesis, John Wiley and Sons, and J. F. W. McOmis: Protective Groups in Organic Chemistry, Plenum Press) as described below.
Where the amino-protecting group is a silyl group, the deprotection reaction is usually carried out by treating with a compound from which a fluorine anion is generated, such as tetrabutylammonium fluoride, hydrofluoric acid, hydrofluoric acid-pyridine or potassium fluoride.
The solvent used in the above-mentioned reaction is not particularly limited provided that it has no adverse effect on the reaction. Examples of preferable solvents include ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or di(ethylene glycol)dimethyl ether.
The reaction temperature and reaction time are not particularly limited. The deprotection reaction is usually carried out at a temperature of from 0xc2x0 C. to 50xc2x0 C. in a period of from 10 minutes to 18 hours.
Where the amino-protecting group is either an aliphatic acyl group, an aromatic acyl group, an alkoxycarbonyl group or a substituted methylene group that forms a Schiff base, the protecting group can be removed by treating with an acid or a base in the presence of an aqueous solvent.
The acid used in the above-mentioned reaction is not particularly limited provided that it is usually used as an acid and has no adverse effect on the reaction. Examples of suitable acids include inorganic acids such as hydrobromic acid, hydrochloric acid, sulfuric acid, perchloric acid or phosphoric acid, and hydrochloric acid is preferable.
The base that can be used in the above-described reaction is not particularly limited provided that it has no adverse effect on the structural moieties other than the protecting group.
Examples of preferred bases include alkali metal carbonates such as lithium carbonate, sodium carbonate or potassium carbonate; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide or potassium hydroxide; alkali metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide or potassium t-butoxide; or ammonia solutions such as ammonia solution or concentrated methanolic ammonia solution.
The solvent used in the above-mentioned reaction is not particularly limited provided that it is usually used in hydrolysis reactions. Examples of suitable solvents include alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerol, octanol, cyclohexanol or methyl cellosolve; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or di(ethylene glycol)dimethyl ether, water; or mixtures of water and one or more organic solvents thereof. Ethers (particularly dioxane) are preferable.
The reaction temperature and reaction time mainly depend on the starting material compounds, the solvent and the acid or base employed in the reaction but are not particularly limited. The deprotection reaction is usually carried out at a temperature of from 0xc2x0 C. to 150xc2x0 C. in a period of from 1 to 10 hours in order to lower the occurrence of the side reactions.
Where the amino-protecting group is an aralkyl group or an aralkyloxycarbonyl group, the protecting group is usually and preferably removed by treating with a reducing agent in an inert solvent (preferably by catalytic hydrogenation with a catalyst at room temperature) or treating with an oxidizing agent.
The solvent used in the deprotection reaction by the catalytic hydrogenation is not particularly limited provided that it has no adverse effect on the reaction. Examples of suitable solvents include aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as toluene, benzene or xylene; esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate or diethyl carbonate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or di(ethylene glycol)dimethyl ether, alcohols such as methanol, ethanol, n-propanol, isopropanol, r-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerol, octanol, cyclohexanol or methyl cellosolve; organic acids such as acetic acid; water, or mixtures of water and one or more organic solvents thereof. Of these solvents, alcohols, ethers, organic acids or water are preferred, and alcohols or organic acids are particularly preferred.
The catalyst used in the deprotection reaction by catalytic hydrogenation is not particularly limited provided that it is usually used in catalytic hydrogenation. Examples of preferable catalysts used in catalytic hydrogenation include palladium-on-charcoal, Raney nickel, platinum oxide, platinum black, rhodium-aluminium oxide, triphenylphosphine-rhodium chloride and palladium-barium sulfate.
The pressure in catalytic hydrogenation is not particularly limited, but the deprotection by catalytic hydrogenation is usually carried out at a pressure of from 1 to 10 atmospheric pressure.
The reaction temperature and reaction time mainly depend on the starting material compounds, the catalyst and the solvent employed in the reaction. The deprotection reaction is usually carried out at a temperature of from 0xc2x0 C. to 100xc2x0 C. in a period of from 5 minutes to 24 hours.
The solvent used in the deprotection by oxidation reaction is not particularly limited provided that it has no adverse effect on the reaction. This reaction is preferably carried out in an organic solvent containing water.
Examples of the preferable organic solvent used in this reaction include halogenated hydrocarbons such as chloroform, methylene chloride, 1,2-dichloroethane or carbon tetrachloride; nitrites such as acetonitrile; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or di(ethylene glycol)dimethyl ether, ketones such as acetone; amides such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; sulfoxides such as dimethyl sulfoxide; or sulfolane.
Halogenated hydrocarbons, ethers or sulfoxides particularly halogenated hydrocarbons or sulfoxides) are preferable.
The oxidizing agent used in this reaction is not particularly limited provided that it is usually used for oxidation reactions. Examples of the preferable oxidizing agents used in this reaction include potassium persulfate, sodium persulfate, ammonium cerium nitrate (CAN) and 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ).
The reaction temperature and reaction time mainly depend on the starting material compounds, the catalyst and the solvent employed in the reaction. The deprotection reaction is usually carried out at a temperature of from 0xc2x0 C. to 150xc2x0 C. in a period of from 10 minutes to 24 hours.
Alternatively, where the amino-protecting group is an aralkyl group, the protecting group may be removed using an acid.
The acid used in the above-mentioned reaction is not particularly limited provided that it is usually used as the acid catalyst in common reactions. Examples of a suitable acid include Brxc3x6nsted acids including inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid or phosphoric acid; or organic acids such as acetic acid, formic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, trifluoroacetic acid or trifluoromethanesulfonic acid; Lewis acids such as zinc chloride, tin tetrachloride, boron trichloride, boron trifluoride or boron tribromide; and acidic ion-exchange resins. Inorganic and organic acids (most preferably hydrochloric acid, acetic acid or trifluoroacetic acid) are preferable.
The inert solvent used in the first stage of the above-mentioned reaction is not particularly limited provided that it has no adverse effect on the reaction. Examples of suitable solvents include aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether, aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as chloroform, methylene chloride, 1,2-dichloroethane or carbon tetrachloride; esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate or diethyl carbonate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or di(ethylene glycol)dimethyl ether; alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerol, octanol, cyclohexanol or methyl cellosolve; amides such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; water; or mixtures of water and solvents thereof or of solvents thereof. Of these solvents, ethers, alcohols or water (most preferably dioxane, tetrahydrofuran, ethanol or water) are preferred.
The reaction temperature mainly depends on the starting material compounds, the acid and the solvent employed in the reaction. The reaction is usually carried out at a temperature of from xe2x88x9220xc2x0 C. to the boiling point of the solvent used (preferably from 0xc2x0 C. to 100xc2x0 C.).
The reaction time mainly depends on the starting material compounds, the acid, the solvent and the reaction temperature employed in the reaction. The reaction is usually carried out in a period of from 15 minutes to 48 hours (preferably from 30 minutes to 20 hours).
Where the amino-protecting group is an alkenyloxycarbonyl group, the deprotection reaction is usually carried out by treating with a base under the same reaction conditions as that described for the deprotection of the amino group protected with an aliphatic acyl group, an aromatic acyl group, an alkoxycarbonyl group or a substituted methylene group which forms a Schiff base.
Where the amino-protecting group is an allyoxycarbonyl group, however, the deprotection is commonly carried out by catalytic hydrogenation using a palladium, triphenylphosphine or nickel tetracarbonyl derivative, since this deprotection procedure is simple and the occurrence of side reactions is low.
Where the hydroxyl-protecting group is a silyl group, the protecting group is usually removed by treating with a compound from which a fluorine anion is generated, such as tetrabutylammonium fluoride, hydrofluoric acid, hydrofluoric acid-pyridine and potassium fluoride or by treating with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid or phosphoric acid; or an organic acid such as acetic acid, formic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, trifluoroacetic acid or trifluoromethanesulfonic acid.
In some cases of the removal of the protecting group by a fluorine anion, the reaction is accelerated by the addition of an organic acid such as formic acid, acetic acid or propionic acid.
The inert solvent used in the above-mentioned reaction is not particularly limited provided that it has no adverse effect on the reaction. Examples of preferable solvents include ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or di(ethylene glycol)dimethyl ether; nitrites such as acetonitrile or isobutyronitrile; organic acids such as acetic acid; water; or mixtures of solvents thereof.
The reaction temperature and reaction time mainly depend on the starting material compound, the catalyst and the solvent employed in the reaction. The reaction is usually carried out at a temperature of from 0xc2x0 C. to 100xc2x0 C. (preferably from 10xc2x0 C. to 50xc2x0 C.) in a period of from 1 to 24 hours.
Where the hydroxyl-protecting group is an aralkyl group or an aralkyloxycarbonyl group, the protecting group is usually and preferably removed by treating with a reducing agent (preferably by catalytic hydrogenation with a catalyst at room temperature) in an inert solvent or by treating with an oxidizing agent.
The solvent used in the deprotection reaction by catalytic hydrogenation is not particularly limited provided that it has no adverse effect on the reaction. Examples of suitable solvents include aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as toluene, benzene or xylene; esters such as ethyl acetate or propyl acetate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or di(ethylene glycol)dimethyl ether; alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerol, octanol, cyclohexanol or methyl cellosolve; amides such as formamide, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone or hexamethylphosphoric triamide; aliphatic acids such as formic acid or acetic acid; water, or mixtures of solvents thereof. Of these solvents, alcohols particularly methanol) are preferred.
The catalyst used in the deprotection reaction by catalytic hydrogenation is not particularly limited provided that it is usually used in catalytic hydrogenation. Examples of suitable catalysts used in the catalytic hydrogenation include palladium-on-charcoal, palladium black, Raney nickel, platinum oxide, platinum black, rhodium-aluminium oxide, triphenylphosphine-rhodium chloride and palladium-barium sulfate, and palladium-on-charcoal is preferred.
The pressure in the catalytic hydrogenation is not particularly limited, but the deprotection by catalytic hydrogenation is usually carried out at a pressure of from 1 to 10 atmospheric pressure.
The reaction temperature and reaction time mainly depend on the starting material compound, the catalyst and the solvent employed in the reaction. The deprotection reaction is usually carried out at a temperature of from 0xc2x0 C. to 100xc2x0 C. in a period of from 5 minutes to 48 hours, and preferably carried out at a temperature of from 20xc2x0 C. to 70xc2x0 C. in a period of from 1 to 24 hours.
The solvent used in the deprotection by oxidation reaction is not particularly limited provided that it has no adverse effect on the reaction. This reaction is preferably carried out in an organic solvent containing water.
Examples of the preferable organic solvent used in this reaction include ketones such as acetone; halogenated hydrocarbons such as methylene chloride, chloroform or carbon tetrachloride; nitriles such as acetonitrile; ethers such as diethyl ether, tetrahydrofuran or dioxane; amides such as dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; or sulfoxides such as dimethyl sulfoxide.
The oxidizing agent used in this reaction is not particularly limited provided that it is usually used for oxidation reactions. Examples of the preferable oxidizing agents used in this reaction include potassium persulfate, sodium persulfate, ammonium cerium nitrate (CAN) and 2,3-dichloro-5,6-dicyano-phenzoquinone (DDQ).
The reaction temperature and reaction time mainly depend on the starting material compound, the catalyst and the solvent employed in the reaction. The deprotection reaction is usually carried out at a temperature of from 0xc2x0 C. to 150xc2x0 C. in a period of from 10 minutes to 24 hours. Alternatively, the protecting group can also be removed by treating with alkali metals such as metallic lithium or metallic sodium at a temperature of from xe2x88x9278xc2x0 C. to 0xc2x0 C. in liquid ammonia or alcohol such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerol, octanol, cyclohexanol or methyl cellosolve.
Additionally, the protecting group can also be removed by treating with aluminium chloride-sodium iodide or an alkylsilyl halide such as trimethylsilyl iodide in a solvent.
The solvent used in the deprotection reaction is not particularly limited provided that it has no adverse effect on the reaction. Examples of the preferable solvents used in this reaction include halogenated hydrocarbons such as methylene chloride, chloroform or carbon tetrachloride; nitrites such as acetonitrile; or mixtures of solvents thereof.
The reaction temperature and reaction time mainly depend on the starting material compound and the solvent employed in the reaction. The deprotection reaction is usually carried out at a temperature of from 0xc2x0 C. to 50xc2x0 C. in a period of from 5 minutes to 72 hours.
Where a sulfur atom is contained in a compound subjected to the deprotection reaction, aluminium chloride-sodium iodide is preferably used.
Where the hydroxyl-protecting group is an aliphatic acyl group, an aromatic acyl group or an alkoxycarbonyl group, the protecting group is removed by treating with a base in a solvent.
The base that can be used in the above-described reaction is not particularly limited provided that it has no adverse effect on the structural moieties other than the protection group.
Examples of preferable bases include alkali metal carbonates such as lithium carbonate, sodium carbonate or potassium carbonate; alkali metal bicarbonates such as lithium bicarbonate, sodium bicarbonate or potassium bicarbonate; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide or potassium hydroxide; alkali metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide or potassium t-butoxide; or ammonia solutions such as ammonia solution or concentrated methanolic ammonia solution. Alkali metal hydroxides, alkali metal alkoxides or ammonia solutions are preferred, and alkali metal hydroxides and alkali metal alkoxides are particularly preferred.
The solvent used in the above-mentioned reaction is not particularly limited provided that it is usually used in hydrolysis reactions. Examples of preferable solvents include ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or di(ethylene glycol)dimethyl ether; alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerol, octanol, cyclohexanol or methyl cellosolve; water, or mixtures of solvents thereof.
The reaction temperature and reaction time mainly depend on the starting material compounds, the base and the solvent employed in the reaction but are not particularly limited. The deprotection reaction is usually carried out at a temperature of from xe2x88x9220xc2x0 C. to 150xc2x0 C. in a period of from 1 to 10 hours in order to lower the occurrence of the side reactions.
Where the hydroxyl protecting group is any of an alkoxymethyl group, tetrahydropyranyl group, tetrahydrothiopyranyl group, tetrahydrofuranyl group, tetrahydrothiofuranyl group or substituted ethyl group, the protecting group is usually removed by treating with an acid in a solvent.
The acid used in this reaction is not particularly limited provided that it is usually used as a Brxc3x8nsted acid or Lewis acid. Examples of preferable Brxc3x8nsted acids include inorganic acids such as hydrogen chloride, hydrochloric acid, sulfuric acid or nitric acid or organic acids such as acetic acid, trifluoroacetic acid, methanesulfonic acid or p-toluenesulfonic acid, and examples of preferable Lewis acids include boron trifluoride. Additionally, strongly acidic cation exchange resins such as Dowex 50W can be also used.
The solvent used in the above-mentioned reaction is not particularly limited provided that it has no adverse effect on the reaction. Examples of suitable solvents include aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether, aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate or diethyl carbonate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or di(ethylene glycol)dimethyl ether, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol glycerol, octanol cyclobexanol or methyl cellosolve; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone or cyclohexanone; water, or mixtures of solvents thereof. Of these solvents, ethers (particularly tetrahydrofuran) and alcohols (particularly methanol) are preferred.
The reaction temperature and reaction time mainly depend on the starting material compounds, the acid and the solvent employed in the reaction. The reaction is usually carried out at a temperature of from xe2x88x9210xc2x0 C. to 200xc2x0 C. (preferably from 0xc2x0 C. to 150xc2x0 C.) in a period of from 5 minutes to 48 hours (preferably from 30 minutes to 10 hours).
Where the hydroxyl-protecting group is an alkenyloxycarbonyl group, the deprotection reaction is usually carried out by treating with a base under the same reaction conditions as that described for the deprotection of the hydroxyl group protected with an aliphatic acyl group, an aromatic acyl group or an alkoxycarbonyl group.
Where the hydroxyl-protecting group is an allyloxycarbonyl group, however, the deprotection reaction is usually and preferably carried out by a catalytic hydrogenation using palladium, triphenylphosphine or bis(methyldiphenylphosphine)(1,5-cyclooctadiene)iridium(I)hexafluorophosphate, since this procedure is simple and the occurrence of side reactions is low.
Where the carboxyl-protecting group is a C1-C6 alkyl group or a C1-C6 alkyl group substituted with one to three C6-C10 aryl substituents which is optionally substituted with C1-C6 alkyl, C1-C10 alkoxy, nitro, halogen or cyano, the deprotection reaction is usually carried out by treatment with a base under the same reaction conditions as that described for the deprotection of the hydroxyl group protected with an aliphatic acyl group, an aromatic acyl group or an alkoxycarbonyl group.
In addition, the removal of the amino-, the hydroxyl- and/or the carboxyl-protecting groups can be carried out by conducting the suitable deprotection reactions successively without any special order, if necessary.
The procedures for protecting the amino group and the hydroxyl group depend on the nature of the protecting group used, but the protection is generally carried out according to the known procedures commonly used in organic synthetic chemistry as shown below.
In the case of a compound (I) where R1 and R2 are each a hydrogen atom, the protection of the amino group can be carried out by the reaction of the relevant compound with a compound of general formula (XII) shown below in an inert solvent (examples of a preferable solvent include ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or di(ethylene glycol)dimethyl ether; or alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerol, octanol, cyclohexanol or methyl cellosolve) in the presence or absence of a base (organic amines such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine or pyridine) at a temperature of from 0xc2x0 C. to 50xc2x0 C. (preferably at room temperature) in a period of from 30 minutes to 10 hours (preferably from 1 to 5 hours).
R1axe2x80x94Zxe2x80x83xe2x80x83(XII)
[in the formula, R1a is an amino-protecting group (as defined earlier) and Z is a halogen atom].
In the case of a compound (I) where R3 is a hydrogen atom, the protection of the hydroxyl group can be carried out by the reaction of the relevant compound with a compound of general formula (XIII) shown below in an inert solvent (examples of a preferable solvent include halogenated hydrocarbons such as chloroform, methylene chloride, 1,2-dichloroethane or carbon tetrachloride; amides such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; or sulfoxides such as dimethylsulfoxide) in the presence of a base (examples of a preferable base include alkali metal hydrides such as lithium hydride, sodium hydride or potassium hydride; and organic amines such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine or pyridines) at a temperature of from 0xc2x0 C. to 50xc2x0 C. (preferably at around room temperate) in a period of from 30 minutes to 24 hours preferably from 1 to 24 hours).
R3axe2x80x94Zxe2x80x83xe2x80x83(XIII)
[in the formula, R3a is a hydroxyl-protecting group (as defined earlier) and Z is as defined earlier].
Furthermore, the removal of the amino-, the hydroxyl- and/or the carboxyl-protecting groups and the protection of the amino group, the hydroxyl group and/or the carboxyl group can be carried out by conducting the suitable deprotection or protection reactions successively without any special order, if necessary.
After the completion of the reaction, the target compounds (I) of the reaction may be collected from the reaction mixture according to the conventional method. For ex ample, the target compound can be obtained by conducting the following steps successively: appropriately neutralizing the reaction mixture; removing, if any, insoluble material(s) by filtration; adding an organic solvent which is not miscible with water (e.g. ethyl acetate); separating the organic layer containing the target compound; washing the extract with, for example, water and then drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate or the like; and removing solvent by evaporation. The target compound can be isolated and purified, if necessary, by a suitable combination of conventional methods commonly used for the separation purification of organic compounds such as recrystallization, reprecipitation and chromatography using appropriate eluent(s).
In Step A9, a compound of general formula (a) is synthesized by hydrolyzing a compound (X) with a base and then, if necessary, by conducting successively the removal of an amino, a hydroxyl- and/or a carboxyl-protecting group in R1, R2, R3, R5a, R6a and R7a, the protection of an amino group in R1 and/or R2, and/or the protection of a hydroxyl group in R3. This step is carried out in a similar manner to that described earlier in Step A8 of the method A.
In Step A10, a compound of general formula (Ic) is synthesized by reducing the ester group of a compound (IX) and then, if necessary, by conducting successively the removal of an amino, a hydroxyl- and/or a carboxyl-protecting group in R1, R2, R3, R5a, R6a and R7a, the protection of an amino group in R1 and/or R2, and/or the protection of a hydroxyl group in R3. The reduction of the ester group of the compound (IX) is carried out in a similar manner to that described earlier in Step A6 of the method A.
In Method B, a compound (Id) which is a compound (I) where X is an ethynylene group, a compound (Ie) which is a compound (I) where X is a vinylene group, a compound (If) which is a compound (I) where X is an ethylene group, a compound (Ig) which is a compound (I) where X is a xe2x80x9cxe2x80x94COxe2x80x94CH2xe2x80x94xe2x80x9d group, a compound (Ig-1) which is a compound (I) where X is a xe2x80x9cxe2x80x94COxe2x80x94CH2xe2x80x94xe2x80x9d group and R1 is a xe2x80x9cxe2x80x94CO2R10xe2x80x9d group, a compound (Ih) which is a compound (I) where X is a xe2x80x9cxe2x80x94CH(OH)xe2x80x94CH2xe2x80x94xe2x80x9d group, a compound (Ii) which is a compound (I) where X is an aryl group or an aryl group substituted with 1-3 substituents selected from the substituent group a, and a compound (Ij) which is a compound (I) where X is an oxygen atom or a sulfur atom are prepared. 
In the above scheme, R1, R2, R3, R4, R5, R5a, R6, R6a, R7, R7a, R10, Y and n are as defined earlier, Xa is an oxygen atom or a sulfur atom, Ya is a C1-C10 alkylene group or a C1-C10 alkylene group substituted with 1-3 substituents selected from the substituent groups a and b, ring A is an aryl group or an aryl group substituted with 1-3 substituents selected from the substituent group a, and W is a group having the following general formulae. 
[in the above formulae, R4 and R10 are as defined earlier, Rxe2x80x2 and Rxe2x80x3 are the same or different and each is independently a lower alkyl group, an aryl group or an aryl group substituted with 1-3 substituents selected from the substituent group a].
In Step B1, a compound of general formula (XVI) is synthesized by the Sonogashira coupling reaction of a compound of general formula (XIV) and a compound of general formula (XV) in an inert solvent in the presence of a base and palladium catalyst.
The solvent used in the above-mentioned reaction is not particularly limited provided that it has no adverse effect on the reaction. Examples of suitable solvents include aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether, aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate or diethyl carbonate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or di(ethylene glycol)dimethyl ether, ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone or cyclohexanone; nitriles such as acetonitrile or isobutyronitrile; amides such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; and sulfoxides such as dimethyl sufoxide or sulfolane. Ethers, amides or sufoxides (particularly amides or ethers) are preferable. In some cases, the reaction is accelerated by the addition of a small amount of water to the reaction solvent.
The base used in the above-mentioned reaction is, for example, the same as that used for the conversion of the hydroxyl group into the leaving group described in Step A2 of the method A, and organic amines (most preferably triethylamine) are preferred.
The palladium catalyst used in the above-mentioned reaction is not particularly limited provided that it is usually used for the Sonogashira coupling reaction. Examples of the preferred catalysts include palladium salts such as palladium acetate, palladium chloride or palladium carbonate; and palladium complexes such as bis(triphenylphosphine)palladium chloride complex formed from complexes with ligands.
Furthermore, the yield can be improved by the addition of cuprous chloride or benzyltriethylammonium chloride as an additive.
The reaction temperature mainly depends on the starting material compounds, the base and the solvent employed in the reaction. The reaction is usually carried out at a temperature of from xe2x88x9220xc2x0 C. to 200xc2x0 C. (preferably from 0xc2x0 C. to 120xc2x0 C.).
The reaction time mainly depends on the starting material compounds, the base, the solvent and the reaction temperature employed in the reaction. The reaction is usually carried out in a period of from 5 minutes to 48 hours preferably from 15 minutes to 24 hours).
After the completion of the reaction, the target compounds (XVI) of this reaction may be collected from the reaction mixture according to conventional methods. For example, the target compound can be obtained by conducting the following steps successively: appropriately neutralizing the reaction mixture; removing, if any, insoluble material(s) by filtration; adding an organic solvent which is not miscible with water (e.g. ethyl acetate); separating the organic layer containing the target compound; washing the extract with, for example, water and then drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate or the like; and removing solvent by evaporation. The target compound can be isolated and purified, if necessary, by a suitable combination of the conventional methods commonly used for the separation/purification of organic compounds such as recrystallization, reprecipitation and chromatography using appropriate eluent(s).
In Step B2, a compound of general formula (Id) is prepared as follows. Where W of a compound (XVI) is a (W-1) group, the compound of general formula (Id) is synthesized in a similar manner to that described either in steps A7 and A8 of the method A or step A9 of the method A. On the other hand, where W of a compound (XVI) is a (W-2) group or a (W-3) group, the compound (Id) is prepared in a similar manner to that described earlier in step A8 of the method A.
In Step B3, a compound of general formula (XVII) is prepared by conducting the reaction of a compound (XV) with catecholborane and subsequently by conducting the Suzuki coupling reaction of the resulting product and a compound (XIV).
The reaction temperature for the reaction of the compound (XV) with catecholborane mainly depends on the starting material compounds, the base and the solvent employed in the reaction. The reaction is usually carried out at a temperature of from 0xc2x0 C. to 150xc2x0 C. (preferably from 10xc2x0 C. to 100xc2x0 C.).
The reaction time for the reactions of the compound (XV) with catecholborane mainly depends on the starting material compounds, the base, the solvent and the reaction temperature employed in the reaction. The reaction is usually carried out in a period of from 15 minutes to 24 hours (preferably from 30 minutes to 12 hours).
The Suzuki coupling reaction is carried out in a similar manner to that described for the Sonogashira coupling reaction in step B1 of the method B.
The solvent used in the above-mentioned reaction is the same as that used in Step B1 of the method B, and aromatic hydrocarbons (most preferably toluene) are preferred.
The base used in the above-mentioned reaction is, for example, the same as that used for the conversion of the hydroxyl group into the leaving group described in Step A2 of the method A, and alkali metal alkoxides (most preferably sodium ethoxide) are preferred.
The palladium catalyst used in the above-mentioned reaction is the same as that used in Step B1 of the method B, and palladium complexes (most preferably bis(triphenylphosphine)palladium chloride complex) are preferred.
In Step B4, a compound of general formula (Ic) is prepared as follows. Where W of a compound (XVII) is a (W-1) group, the compound of general formula (Ie) is synthesized in a similar manner to that described either in steps A7 and A8 of the method A or step A9 of the method A. On the other hand, where W of a compound (XVII) is a (W-2) group or a (W-3) group, the compound (Ie) is prepared in a similar manner to that described earlier in step A8 of the method A.
In Step B5, a compound of general formula (XVIII) is prepared by reducing a compound (XVI) in an inert solvent (preferably a catalytic hydrogenation at room temperature in the presence of a catalyst).
The solvent used in the deprotection by the catalytic hydrogenation is not particularly limited provided that it has no adverse effect on the reaction. Examples of suitable solvents include aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as toluene, benzene or xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate or diethyl carbonate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or di(ethylene glycol)dimethyl ether, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerol, octanol, cyclohexanol or methyl cellosolve; organic acids such as acetic acid or hydrochloric acid; water; or mixtures of water and solvents thereof. Of these solvents, alcohols and ethers (particularly methanol) are preferred.
The catalyst used in the deprotection by the catalytic hydrogenation is not particularly limited provided that it is usually used in catalytic hydrogenation. Examples of preferred catalysts used in catalytic hydrogenation include palladium-on-charcoal, Raney nickel, platinum oxide, platinum black, rhodium-aluminium oxide, triphenylphosphine-rhodium chloride and palladium-barium sulfate.
The reaction temperature mainly depends on the starting material compounds, the base and the solvent employed in the reaction. The reaction is usually carried out at a temperature of from xe2x88x9220xc2x0 C. to 200xc2x0 C. (preferably from 0xc2x0 C. to 100xc2x0 C.).
The reaction time mainly depends on the starting material compounds, the base, the solvent and the reaction temperature employed in the reaction. The reaction is usually carried out in a period of from 5 minutes to 96 hours (preferably from 15 minutes to 72 hours).
After the completion of the reaction, the target compounds (XVIII) of this reaction may be collected from the reaction mixture according to conventional methods. For example, the target compound can be obtained by conducting the following steps successively: appropriately neutralizing the reaction mixture; removing, if any, insoluble material(s) by filtration; adding an organic solvent which is not miscible with water (e.g. ethyl acetate); separating the organic layer containing the target compound; washing the extract with, for example, water and then drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate or the like; and removing solvent by evaporation. The target compound can be isolated and purified, if necessary, by a suitable combination of the conventional methods commonly used for the separation/purification of organic compounds such as recrystallization, reprecipitation and chromatography using appropriate eluent(s).
In Step B6, a compound of general formula (If) is prepared as follows. Where W of a compound (XVII) is a (W-1) group, the compound of general formula (If) is synthesized in a similar manner to that described either in steps A7 and A8 of the method A or step A9 of the method A. On the other hand, where W of a compound (XVIII) is a (W-2) group or a (W-3) group, the compound (If) is prepared in a similar manner to that described earlier in step A8 of the method A.
In Step B7, a compound of genera) formula (XIX) is prepared as follows. Where W of a compound (XVI) is a (W-1) group, the compound of general formula (XIX) is synthesized in a similar manner to that described either in steps A7 and A8 of the method A or step A9 of the method A. On the other hand, where W of a compound (XVI) is a (W-2) group or a (W-3) group, the compound (XIX) is prepared in a similar manner to that described earlier in step A8 of the method A.
In Step B8, a compound of general formula (Ig) is prepared by treating a compound (XIX) in an inert solvent by procedures comprising the addition reaction of water in the presence of an acid catalyst or the oxymercuration reaction with mercury oxide and then, if necessary, by conducting successively the removal of an amino-, a hydroxyl- and/or a carboxyl-protecting group in R1, R2, R3, R5a, R6a and R7a, the protection of an amino group in R1 and/or R2, and/or the protection of a hydroxyl group in R3.
The solvent used in the above-mentioned reaction is not particularly limited provided that it has no adverse effect on the reaction. Examples of suitable solvents include aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether, aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate or diethyl carbonate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or di(ethylene glycol)dimethyl ether, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerol, octanol, cyclohexanol or methyl cellosolve; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone, cyclohexanone; water, or mixtures of solvents thereof. Of these solvents, alcohols (particularly methanol) are preferred.
The acid catalyst used in the above-mentioned reaction is not particularly limited provided that it is usually used as an acid catalyst in common reactions. Examples of suitable acids include Brxc3x6nsted acids including inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid or phosphoric acid; and organic acids such as acetic acid, formic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, trifuoroacetic acid or trifluoromethanesulfonic acid; Lewis acids such as zinc chloride, tin tetrachloride, boron trichloride, boron tribroride or boron tribromide; and acidic ion-exchange resins. Inorganic acids (most preferably sulfuric acid) are preferable.
The reaction temperature mainly depends on the starting material compounds, the base and the solvent employed in the reaction. The reaction is usually carried out at a temperature of from xe2x88x9220xc2x0 C. to 200xc2x0 C. (preferably from 0xc2x0 C. to 100xc2x0 C.).
The reaction time mainly depends on the starting material compounds, the base, the solvent and the reaction temperature employed in the reaction. The reaction is usually carried out in a period of from 5 minutes to 96 hours (preferably from 15 minutes to 72 hours).
The removal of an amino-, a hydroxyl- and/or a carboxyl-protecting group in R1, R2, R3, R5a, R6a and R7a, the protection of an amino group in R1 and/or R2, and/or the protection of a hydroxyl group in R3, all of which are, if necessary, carried out, are performed in a similar manner to that described in step A8 of the method A.
In Step B9, a compound of general formula (Ig-1) is prepared by treating a compound (XVIa) in an inert solvent by procedures comprising the addition reaction of water in the presence of an acid catalyst or the oxymercuration reaction with mercury oxide and then, if necessary, by conducting successively the removal of an amino-, a hydroxyl- and/or a carboxyl-protecting group in R1, R2, R3, R5a, R6a and R7a, and/or the protection of a hydroxyl group in R3. This step is carried out in a similar manner to that described earlier in Step B8 of the method B.
In Step B10, a compound of general formula (XX) is prepared by treating a compound (XIX) in an inert solvent by procedures comprising the addition reaction of water in the presence of an acid catalyst or the oxymercuration reaction with mercury oxide and then, if necessary, by conducting successively the removal of an amino-, a hydroxyl- and/or a carboxyl-protecting group in R1, R2, R3, R5a, R6a and R7a, the protection of an amino group in R1 and/or R2, and/or the protection of a hydroxyl group in R3. This step is carried out in a similar manner to that described earlier in Step B8 of the method B.
In Step B11, a compound of general formula (Ih) is synthesized by reducing a compound (XX) in an inert solvent and then, if necessary, by conducting successively the removal of an amino-, a hydroxyl- and/or a carboxyl-protecting group in R1, R2, R3, R5a, R6a and R7a, the protection of an amino group in R1 and/or R2, and/or the protection of a hydroxyl group in R3.
The inert solvent used in the above-mentioned reaction is not particularly limited provided that it has no adverse effect on the reaction. Examples of suitable solvents include aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as chloroform, methylene chloride, 1,2-dichloroethane or carbon tetrachloride; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or di(ethylene glycol)dimethyl ether; alcohols such as methanol, ethanol, n-propanol isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerol, octanol, cyclohexanol or methyl cellosolve; or mixtures of solvents thereof. Of these solvents, ethers or alcohols (particularly methanol or ethanol) are preferred.
The reducing agent used in the above-mentioned reaction is, for example, an alkali metal borohydride such as sodium borohydride, lithium borohydride or sodium cyanoborohydride; or an aluminium hydride such as diisobutylaluminium hydride, lithium aluminium hydride or triethoxyaluminium lithium hydride. The preferred example is an alkali metal borohydride (sodium cyanoborohydride).
The reaction temperature mainly depends on the starting material compounds, the base and the solvent employed in the reaction. The reaction is usually carried out at a temperature of from xe2x88x9210xc2x0 C. to 100xc2x0 C. (preferably from xe2x88x9220xc2x0 C. to 20xc2x0 C.).
The reaction time mainly depends on the starting material compounds, the base, the solvent and the reaction temperature employed in the reaction. The reaction is usually carried out in a period of from 10 minutes to 48 hours (preferably from 30 minutes to 12 hours).
The removal of an amino-, a hydroxyl- and/or a carboxyl-protecting group in R1, R2, R3, R5a, R6a and R7a, the protection of an amino group in R1 and/or R2, and/or the protection of a hydroxyl group in R3, all of which are, if necessary, carried out, are performed in a similar manner to that described in step AS of the method A.
After the completion of the reaction, the target compounds (Ih) of this reaction may be collected from the reaction mixture according to conventional methods. For example, the target compound can be obtained by conducting the following steps successively: appropriately neutralizing the reaction mixture; removing, if any, insoluble material(s) by filtration; adding an organic solvent which is not miscible with water (e.g. ethyl acetate); separating the organic layer containing the target compound; washing the extract with, for example, water and then drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate or the like; and removing solvent by evaporation. The target compound can be isolated and purified, if necessary, by a suitable combination of the conventional methods commonly used for the separation/purification of organic compounds such as recrystallization, reprecipitation and chromatography using appropriate eluent(s).
In Step B12, a compound of general formula (XXII) is prepared by conducting the Suzuki coupling reaction of a compound (XXI) and a compound (XIV). This step is carried out in a similar manner to that described for the Sonogashira coupling reaction in Step B3 of the method B.
In Step B13, a compound of general formula (Ii) is prepared as follows. Where W of a compound (XXII) is a (W-1) group, the compound of general formula (Ii) is synthesized in a similar manner to that described either in steps A7 and A8 of the method A or step A9 of the method A. On the other hand, where W of a compound (XXII) is a (W-2) group or a (W-3) group, the compound (Ii) is prepared in a similar manner to that described earlier in step A8 of the method A.
In Step B14, a compound of general formula (XXIV) is prepared by the reaction of a compound (XIV) with an alkali metal salt of a compound (XXIII) under conditions without solvent or in an inert solvent in the presence of a copper catalyst. This step is carried out by the procedures, for example, described in J. Heterocyclic. Chem., 20, 1557 (1983).
The solvent used in the above-mentioned reaction is not particularly limited provided that it has no adverse effect on the reaction. Examples of suitable solvents include ethers such as diethyl ether, dioxane, tetrahydrofuran, dimethoxyethane, or di(ethylene glycol)dimethyl ether, or pyridines such as pyridine, picoline, lutidine or collidine. The reaction is carried out preferably under conditions without solvent.
The copper catalyst used in the above-mentioned reaction is, for example, cuprous iodide, cuprous bromide, cuprous oxide or cupric oxide, and cuprous oxide is preferred.
The alkali metal salt of the compound (XXIII) used in the above-mentioned reaction is prepared by treating the compound of general formula (XXII) and an alkali metal or alkali metallic compound. Examples of suitable alkali metals include metallic lithium, metallic sodium or metallic potassium, and examples of suitable alkali metallic compounds include alkali metal hydrides such as lithium hydride, sodium hydride or potassium hydride. The alkali metal salt of the compound (XXIII) is preferably prepared using metallic sodium.
Furthermore, the yield can be improved by the addition of potassium iodide as an additive.
The reaction temperature mainly depends on the starting material compounds, the catalyst and the solvent employed in the reaction. The reaction is usually carried out at a temperature of from room temperature to 150xc2x0 C. (preferably from 60xc2x0 C. to 120xc2x0 C.).
The reaction time mainly depends on the starting material compounds, the catalyst and the solvent employed in the reaction. The reaction is usually carried out in a period of from 1 hour to 7 days (preferably from 3 hours to 72 hours).
After the completion of the reaction, the target compounds (XXIV) of this reaction may be collected from the reaction mixture according to conventional methods. For example, the target compound can be obtained by conducting the following steps successively: appropriately neutralizing the reaction mixture; removing, if any, insoluble material(s) by filtration; adding an organic solvent which is not miscible with water (e.g. ethyl acetate); separating the organic layer containing the target compound; washing the extract with, for example, water and then drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate or the like; and removing solvent by evaporation. The target compound can be isolated and purified, if necessary, by a suitable combination of the conventional methods commonly used for the separation/purification of organic compounds such as recrystallization, reprecipitation and chromatography using appropriate eluent(s).
In Step B15, a compound of general formula (Ij) is prepared as follows. Where W of a compound (XXIV) is a (W-1) group, the compound of general formula (Ij) is synthesized in a similar manner to that described either in steps A7 and A8 of the method A or step A9 of the method A. On the other hand, where W of a compound (XXIV) is a (W-2) group or a (W-3) group, the compound (Ij) is prepared in a similar manner to that described earlier in step A8 of the method A.
In Step B16, a compound of general formula (XXVI) is prepared by the reaction of a compound of general formula (XIV) with a compound of general formula (XXV). This step is carried out in a similar manner to that described in Step B1 of the method B.
In Step B 17, a compound (XVIb) which is a compound (XVI) where Y is a xe2x80x9cxe2x80x94Yaxe2x80x94Oxe2x80x94xe2x80x9d group is synthesized by condensing a compound (XXVI) and a compound of general formula (XXVII) in an inert solvent by the Mitsunobu reaction.
The reagent used in the Mitsunobu reaction is not particularly limited provided that it is commonly used in the Mitsunobu reaction. Examples of preferred reagents include combinations of azo compounds including di(lower alkyl) azodicarboxylates such as diethyl azodicarboxylate or diisopropyl azodicarboxylate; or azodicarbonyl derivatives such as 1,1xe2x80x2-(azodicarbonyl)dipiperidine; and phosphines including triarylphosphies such as triphenylphosphine or tri(lower alkyl)phosphines such as tri-n-butylphosphine. The combinations of di(lower alkyl) azodicarboxylates and triarylphosphines are more preferred.
The solvent used in the above-mentioned reaction is not particularly limited provided that it has no adverse effect on the reaction and dissolves the starting materials to some extent
Examples of preferred solvents include aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate or diethyl carbonate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or di(ethylene glycol)dimethyl ether, nitrites such as acetonitrile or isobutyronitrile; amides such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone or hexamethylphosphoric triamide; or sulfoxides such as dimethyl sulfoxide or sulfolane. Aromatic hydrocarbons and ethers are preferable.
The reaction is usually carried out at a temperature of from 20xc2x0 C. to 100xc2x0 C. and preferably from 0xc2x0 C. to 50xc2x0 C.
The reaction time mainly depends on the reaction temperature, the starting material compounds, the reagent or the solvent employed in the reaction. The reaction is usually carried out in a period of from 10 minutes to 3 days and preferably from 30 minutes to 12 hours.
After the completion of the reaction, the target compounds (XVIb) of this reaction may be collected from the reaction mixture according to conventional methods. For example, the target compound can be obtained by conducting the following steps successively: appropriately neutralizing the reaction mixture; removing, if any, insoluble material(s) by filtration; adding an organic solvent which is not miscible with water (e.g. ethyl acetate); separating the organic layer containing the target compound; washing the extract with, for example, water and then drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate or the like; and removing solvent by evaporation. The target compound can be isolated and purified, if necessary, by a suitable combination of the conventional methods commonly used for the separation/purification of organic compounds such as recrystallization, reprecipitation and chromatography using appropriate eluent(s).
Alternatively, the compounds (Id)-(Ij) may be synthesized by hydrolyzing the W group of a compound (XIV) and then by conducting the reaction of the resulting product with a compound (XV), a compound (XXI), a compound (XXIII) or a compound (XXV), respectively.
The compounds (II), (V), (VIII), (XII), (XIII), (XIV), (XV), (XXI), (XXIII), (XXV) and (XXVII) used as the starting materials are either known compounds or can be prepared easily by known or similar methods.
Alternatively, the compounds (II) and (XIV) used as the starting materials can be synthesized by the following methods.
In Method C, a compound (XIV) and a compound (XIVa) which is the compound (XIV) having a bromine atom at the 2-position of the thiophene moiety and a xe2x80x9cxe2x80x94(CH2)n-Wxe2x80x9d group at the 5-position of the thiophene moiety as the substituents, respectively, are prepared. 
In the above scheme, R4, R6a, R7a, R8, R9, R9a, R10, n and W are as defined earlier.
In Step C1, a compound of general formula (XXIX) is prepared by the reaction of a compound of general formula (XXVII) with a reducing agent in an inert solvent in the presence or absence of a base (preferably in the presence of a base). This step is carried out in a similar manner to that described in Step A1 of the method A.
In Step C2, a compound of general formula (XXX) is prepared by converting a hydroxyl group of compound (XXIX) into a leaving group in an inert solvent in the presence of a base and then by conducting an iodination reaction on the resulting leaving group with an iodination agent. This step is carried out in a similar manner to that described in Step A2 of the method A.
In Step C3, a compound of general formula (XXXI) is prepared by the reaction of a compound (XXX) with a compound (V) in an inert solvent in the presence of a base. This step is carried out in a similar manner to that described in Step A3 of the method A.
In Step C4, a compound of general formula (XXXII) is prepared by hydrolyzing a compound (XXXI) with a base in an inert solvent. This step is carried out in a similar manner to that described in Step A4 of the method A.
Step C5 is a step for converting the carboxyl group into a carbamoyl group by the Curtius Rearrangement Reaction, and in this step, a compound of general formula (XXXIII) is synthesized by the reaction of a compound (XXXII) with a diarylphosphoryl azide derivative such as diphenylphosphoryl azide in an inert solvent in the presence of a base and then by the reaction of the resulting product with a compound (VIII). This step is carried out in a similar manner to that described in Step A5 of the method A.
In Step C6, a compound (XIV) is prepared by reducing an ester group of a compound (XXXIII). This step is carried out in a similar manner to that described in Step A6 of the method A.
After the completion of the reaction, the target compounds (XIV) of this reaction may be collected from the reaction mixture according to conventional methods. For example, the target compound can be obtained by conducting the following steps successively: appropriately neutralizing the reaction mixture; removing if any, insoluble material(s) by filtration; adding an organic solvent which is not miscible with water (e.g. ethyl acetate); separating the organic layer containing the target compound; washing the extract with, for example, water and then drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate or the like; and removing solvent by evaporation. The target compound can be isolated and purified, if necessary, by a suitable combination of the conventional methods commonly used for the separation/purification of organic compounds such as recrystallization, reprecipitation and chromatography using appropriate eluent(s).
In Step C7, a compound of general formula (XXXV) is prepared by the reaction of a compound of general formula (XXXIV) with a reducing agent in an inert solvent in the presence or absence of a base (preferably in the presence of a base). This step is carried out in a similar manner to that described in Step A1 of the method A.
In Step C8, a compound of general formula (XXXVI) is prepared by converting a hydroxyl group of compound (XXXV) into a leaving group in an inert solvent in the presence of a base and then by conducting an iodination reaction. This step is carried out in a similar manner to that described in Step A2 of the method A.
In Step C9, a compound of general formula (XXXVI) is prepared by the reaction of a compound (XXXVI) with a compound (V) in an inert solvent in the presence of a base. This step is carried out in a similar manner to that described in Step A3 of the method A.
In Step C10, a compound of general formula (XXVIII) is prepared by hydrolyzing a compound (XXXVII) with a base in an inert solvent. This step is carried out in a similar manner to that described in Step A4 of the method A.
Step C11 is a step for converting the carboxyl group into a carbamoyl group by the Curtius Rearrangement Reaction, and in this step, a compound of general formula (XXXIX) is synthesized by the reaction of the compound (XXXVIII) with a diarylphosphoryl azide derivative such as diphenylphosphoryl azide in an inert solvent in the presence of a base and then by the reaction of the resulting product with a compound (VIII). This step is carried out in a similar manner to that described in Step A5 of the method A.
In Step C12, a compound (XL) is prepared by reducing an ester group of a compound (XXXIX). This step is carried out in a similar manner to that described in Step A6 of the method A.
In Step C13, a compound (XIVa) is prepared by the reaction of a compound (XL) with a brominating agent.
The solvent used in the above-mentioned reaction is not particularly limited provided that it has no adverse effect on the reaction. Examples of suitable solvents include halogenated hydrocarbons such as methylene chloride, chloroform carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or di(ethylene glycol)dimethyl ether, or amides such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide. Amides are preferable and dimethylformamide is most preferable.
The brominating agent used in the above-mentioned reaction is not particularly limited.
Examples of suitable brominating agents include those described in xe2x80x9cComprehensive Organic Transformationxe2x80x9d (Larock, VCH, p 316-317), and N-bromosuccinimide or bromine is preferred.
The reaction temperature mainly depends on the starting material compounds, the brominating agent and the solvent employed in the reaction. The reaction is usually carried out at a temperature of from xe2x88x9278xc2x0 C. to 150xc2x0 C. and preferably from xe2x88x9220xc2x0 C. to 100xc2x0 C.
The reaction time mainly depends on the starting material compounds, the brominating agent, the solvent and the reaction temperature employed in the reaction. The reaction is usually carried out in a period of from 5 minutes to 48 hours and preferably from 30 minutes to 24 hours.
After the completion of the reaction, the target compounds (XIVa) of this reaction maybe collected from the reaction mixture according to conventional methods. For example, the target compound can be obtained by conducting the following steps successively: appropriately neutralizing the reaction mixture; removing, if any, insoluble material(s) by filtration; adding an organic solvent which is not miscible with water (e.g. ethyl acetate); separating the organic layer containing the target compound; washing the extract with, for example, water and then drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate or the like; and removing solvent by evaporation. The target compound can be isolated and purified, if necessary, by a suitable combination of the conventional methods commonly used for the separation/purification of organic compounds such as recrystallization, reprecipitation and chromatography using appropriate eluent(s).
In Method D, a compound (IIa) which is a compound (II) where X is an ethynylene group, a compound (IIb) which is a compound (II) where X is an ethylene group, a compound (IIc) which is a compound (II) where X is a vinylene group, a compound (IId) which is a compound (II) where X is a xe2x80x9cxe2x80x94COxe2x80x94CH2xe2x80x94xe2x80x9d group, a compound (IIe) which is a compound (II) where X is a xe2x80x9cxe2x80x94CH(OH)xe2x80x94CH2xe2x80x94xe2x80x9d group, a compound (IIf) which is a compound (II) where X is an aryl group or an aryl group substituted with 1-3 substituents selected from the substituting moieties a, and a compound (IIg) which is a compound (II) where X is an oxygen atom or a sulfur atom are prepared. 
In the above scheme, R5a, R6a, R7a, R8, n, Xa, Y, Ya and ring A are as defined earlier.
In Step D1, a compound (IIa) is synthesized by the Sonogashira coupling reaction of a compound (XXVIII) and a compound (XV) in an inert solvent in the presence of a base and palladium catalyst. This step is carried out in a similar manner to that described earlier in Step B1 of the method B.
In Step D2, a compound (IIb) is prepared by reducing a compound (IIa) in an inert solvent (preferably by a catalytic hydrogenation at room temperature in the presence of a catalyst). This step is carried out in a similar manner to that described earlier in Step B5 of the method B.
In Step D3, a compound (IIc) is prepared by conducting the reaction of a compound (XV) with catecholborane and subsequently by conducting the Suzuki coupling reaction of the resulting product and a compound (XXVIII). This step is carried out in a similar manner to that described earlier in Step B3 of the method B.
In Step 4, a compound (IId) is prepared by treating a compound (IIa) in an inert solvent by procedures comprising the addition reaction of water in the presence of an acid catalyst or the oxymercuration reaction with mercury oxide. This step is carried out in a similar manner to that described earlier in Step B8 of the method B.
In Step D5, a compound (IIe) is prepared by reducing a compound (IId) in an inert solvent. This step is carried out in a similar manner to that described earlier in Step B11 of the method B.
In Step D6, a compound (IIf) is synthesized by conducting the Suzuki coupling reaction of a compound (XXI) and a compound (XXVIII). This step is carried out in a similar manner to that described earlier in Step B3 of the method B.
In Step D7, a compound (IIg) is prepared by conducting the reaction of a compound (XXVIII) with an alkali metal salt of a compound (XXIII) under conditions without solvent or in an inert solvent in the presence of a copper catalyst. This step is carried out in a similar manner to that described earlier in Step B14 of the method B.
In Step D8, a compound of general formula (XLI) is prepared by the reaction of a compound (XXVIII) with a compound (XXV). This step is carried out in a similar manner to that described earlier in Step B1 of the method B.
In Step D9, a compound (IIa-1) which is a compound (IIa) where Y is a xe2x80x9cxe2x80x94Yaxe2x80x94Oxe2x80x94xe2x80x9d group is prepared by the reaction of a compound (XLI) with a compound (XXVII). This step is carried out in a similar manner to that described earlier in Step B17 of the method B.
In Method e, compounds (XLIVa), (XLIVb), (La) and (Lb), all of which are an intermediate of the compound (I) of the present invention, are prepared. 
In the above scheme, R1, R2, R3, R4a, R11, Ar, m and Z are as defined earlier.
In Step E1, a compound of general formula (XLIVa) or a compound of general formula (XLIVb) is prepared by acylating selectively only one of the hydroxyl groups of a compound of general formula (XXI) with a compound of general formula (XLI) in the presence or absence of a solvent and in the presence of lipase.
The solvent used in the present invention is not particularly limited. The reaction proceeds without any problem even when only the compound (XLIII) is used without any solvent. In addition, a variety of organic solvents and of mixtures of water and organic solvents can be used although the most preferred solvent in this reaction differs due to the nature of the compound used as the starting material. Examples of preferred solvent include ethers such as diisopropyl ether, t-butylmethyl ether, diethyl ether or tetrahydrofuran; aliphatic hydrocarbons such as n-hexane or n-pentane; aromatic hydrocarbons such as benzene or toluene; or halogenated hydrocarbons such as methylene chloride or 1,2-dichloroethane. Ethers are preferred, and diisopropyl ether is most preferred.
The reaction temperature mainly depends on the starting material compounds, the solvent, the lipase and the nature of the compound (XLIII) employed in the reaction. The reaction is usually carried out at a temperature of from xe2x88x9250xc2x0 C. to 50xc2x0 C. and preferably from 0xc2x0 C. to 40xc2x0 C.
The reaction time mainly depends on the starting material compounds, the solvent, lipase and the nature of a compound (XLIII) employed in the reaction. The reaction is usually carried out in a period of from 15 minutes to 150 hours and preferably from 30 minutes to 24 hours.
After the completion of the reaction, the target compounds (XLIVa) and (XLIVb) of this reaction may be collected from the reaction mixture according to conventional methods. For example, after removing, if any, insoluble material(s) by filtration, the target compound can be obtained by concentrating the reaction mixture or conducting the following steps successively: adding an organic solvent which is not miscible with water (e.g. ethyl acetate); separating the organic layer containing the target compound; and then drying over anhydrous sodium sulfate, anhydrous magnesium sulfate or the like; and removing solvent by evaporation.
The target compound obtained can be isolated and purified, if necessary, by conventional methods such as recrystallization, reprecipitation or chromatography using appropriate eluent(s).
In step E2, a compound of general formula (XLV) is prepared by oxidizing the alcohol moiety of a compound (XLIVa) into an aldehyde moiety in an inert solvent in the presence of an oxidizing agent.
The oxidation reaction employed in this step is not particularly limited provided that it can be used for the preparation of the aldehyde moiety from the primary alcohol moiety. Examples of suitable reactions include the Collins oxidation performed using pyridine and chromic acid in methylene chloride; PCC oxidation performed using pyridinium chlorochromate (PCC) in methylene chloride; PDC oxidation performed using pyridinium dichromate (PDC) in methylene chloride; Dimethylsulfoxide (DMSO) oxidation such as Swern oxidation performed using an electrophilic agent (for example, acetic anhydride, trifluoroacetic anhydride, thionyl chloride, sulfuryl chloride, oxalyl chloride, dicyclohexylcarbodiimide, diphenylketene-p-tolylimine; N,N-diethylaminoacetylene; or sulfur trioxide-pyridine complex) and dimethylsulfoxide (DMSO) in methylene chloride; and Manganese oxide oxidation performed using manganese oxide in methylene chloride or benzene.
Of these oxidation reactions, PCC oxidation or Swem oxidation performed in methylene chloride is preferred.
The reaction temperature mainly depends on the starting material compounds, the solvent and the oxidizing agent employed in the reaction. The reaction is usually carried out at a temperature of from xe2x88x9250xc2x0 C. to 50xc2x0 C. and preferably from xe2x88x9210xc2x0 C. to 30xc2x0 C.
The reaction time mainly depends on the starting material compounds, the solvent, the oxidizing agent and the reaction temperature employed in the reaction. The reaction is usually carried out in a period of from 10 minutes to 2 days and preferably from 30 minutes to 24 hours.
For example, after neutralizing the oxidizing agent with sodium hydrogen sulfite and removing, if any, insoluble material(s) by filtrations the target compound can be obtained by concentrating the reaction mixture or conducting the following steps successively: adding an organic solvent which is not miscible with water (e.g. ethyl acetate); separating the organic layer containing the target compound; and then drying over anhydrous sodium sulfate, anhydrous magnesium sulfate or the like; and removing solvent by evaporation.
The target compound obtained can be isolated and purified, if necessary, by conventional methods such as recrystallization, reprecipitation or chromatography using appropriate eluent(s).
In step E3, a compound of general formula (XLVII) is prepared by the reaction of the aldehyde group of the compound (XLV) with a compound of general formula (XLVI) in an inert solvent in the presence of a base.
The solvent used in the above-mentioned reaction is not particularly limited provided that it has no adverse effect on the reaction. Examples of preferred solvents include aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, t-butylmethyl ether or tetrahydrofuran; nitrites such as acetonitrile or isobutyronitrile; amides such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide, or hexamethylphosphoric triamide; or sulfoxides such as dimethyl sulfoxide or sulfolane, and ethers are more preferred.
The base used in the above reaction is not particularly limited provided that it can be used as the base in conventional reactions. Examples of preferred bases include inorganic bases including alkali metal carbonates such as sodium carbonate, potassium carbonate or lithium carbonate; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate or lithium bicarbonate; alkali metal hydrides such as lithium hydride, sodium hydride or potassium hydride; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, barium hydroxide or lithium hydroxide; and alkali metal fluorides such as sodium fluoride or potassium fluoride; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium t-butoxide or lithium methoxide; organic amines such as N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, 4-pyrrolidinopyridine, picoline, 4-N,N-dimethylamino)pyridine, 2,6-di(t-butyl)-4-methylpyridine, N,N-dimethylaniline, N,N-diethylaniline, 1,4-diazaicyclo[4.3.0]octane (DABCO), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or 1,5-diazabicyclo[4.3.0]nona-5-ene (DBN); or organic metallic bases such as butyl lithium, lithium diisopropylamide, lithium bis(trimethylsilyl)amide, and more preferred examples are alkali metal alkoxides, alkali metal hydrides and organic metallic bases.
The reaction temperature mainly depends on the starting material compounds, the solvent, the phosphonium salt and the base employed in the reaction. The reaction is usually carried out at a temperature of from xe2x88x9280xc2x0 C. to 100xc2x0 C. and preferably from xe2x88x9220xc2x0 C. to 50xc2x0 C.
The reaction time mainly depends on the starting material compounds, the solvent, the phosphonium salt and the base employed in the reaction. The reaction is usually carried out in a period of from 10 minutes to 2 days and preferably from 30 minutes to 12 hours.
For example, after neutralizing the reaction mixture with diluted hydrochloric acid and removing, if any, insoluble material(s) by filtration, the target compound can be obtained by concentrating the reaction mixture or conducting the following steps successively: adding an organic solvent which is not miscible with water (e.g. ethyl acetate); separating the organic layer containing the target compound; and then drying over anhydrous sodium sulfate, anhydrous magnesium sulfate or the like; and removing solvent by evaporation.
The target compound obtained can be isolated and purified, if necessary, by conventional methods such as recrystallization, reprecipitation or chromatography using appropriate eluent(s).
In step E4, a compound of general formula (XLVIII) is prepared by hydrolyzing a compound (XLVII) in an inert solvent in the presence of a base.
The solvent used in the above-mentioned reaction is not particularly limited provided that it has no adverse effect on the reaction and dissolves the starting materials to some extent.
Examples of preferred solvents include alcohols such as methanol or ethanol; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride or dichloroethane; ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane or di(ethylene glycol)dimethyl ether, and mixtures of solvents thereof or mixtures of solvents thereof and water. Of these solvents, alcohols and ethers are more preferred.
The base used in the above reaction is not particularly limited provided that it can be used as the base in conventional reactions. Examples of preferred bases include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide or barium hydroxide.
The reaction temperature mainly depends on the starting material compounds, the solvent and the base employed in the reaction. The reaction is usually carried out at a temperature of from xe2x88x9220xc2x0 C. to 200xc2x0 C. and preferably from 0xc2x0 C. to 20xc2x0 C.
The reaction time mainly depends on the starting material compounds, the reaction temperature, the solvent and the base employed in the reaction. The reaction is usually carried out in a period of from 30 minutes to 48 hours and preferably from 1 hour to 24 hours.
For example, after neutralizing the reaction mixture with diluted hydrochloric acid and removing, if any, insoluble material(s) by filtration, the target compound can be obtained by concentrating the reaction mixture or conducting the following steps successively: adding organic solvent which is not miscible with water (e.g. ethyl acetate); separating the organic layer containing the target compound; and then drying over anhydrous sodium sulfate, anhydrous magnesium sulfate or the like; and removing solvent by evaporation.
The target compound obtained can be isolated and purified, if necessary, by conventional methods such as recrystallization, reprecipitation or chromatography using appropriate eluent(s).
Step E5 is a step for preparing a compound of general formula (IL), and in this step, a compound (XLVIII) is converted into the compound (IL) in an inert solvent in the presence of a base.
The solvent used in the above-mentioned reaction is not particularly limited provided that it has no adverse effect on the reaction and dissolves the starting materials to some extent.
Examples of preferred solvents include ethers such as diethyl ether, dioxane, tetrahydrofuran, dimethoxyethane or di(ethylene glycol)dimethyl ether, amides such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone or hexamethylphosphoric triamide; or aromatic hydrocarbons such as benzene, toluene or xylene, and more preferred examples are ethers and amides.
The base used in the above reaction is not particularly limited provided that it can be used as the base in conventional reactions. Examples of preferred bases include inorganic bases including alkali metal hydrides such as lithium hydride, sodium hydride or potassium hydride; and alkali metal fluorides such as sodium fluoride or potassium fluoride; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium t-butoxide or lithium methoxide; or organic metallic bases such as butyl lithium, lithium diisopropylamide or lithium bis(trimethylsilyl)amide, and more preferred examples are alkali metal alkoxides and alkali metal hydrides.
The reaction temperature mainly depends on the starting material compounds, the solvent and the base employed in the reaction. The reaction is usually carried out at a temperature of from xe2x88x9280xc2x0 C. to 100xc2x0 C. and preferably from 0xc2x0 C. to 50xc2x0 C.
The reaction time mainly depends on the starting material compounds, the reaction temperature, the solvent and the base employed in the reaction. The reaction is usually carried out in a period of from 5 minute to 48 hours.
For example, alter neutralizing the reaction mixture with diluted hydrochloric acid and the like and removing, if any, insoluble material(s) by filtration, the target compound can be obtained by concentrating the reaction mixture or conducting the following steps successively: adding an organic solvent which is not miscible with water (e.g. ethyl acetate); separating the organic layer containing the target compound; and then drying over anhydrous sodium sulfate, anhydrous magnesium sulfate or the like; and removing solvent by evaporation.
The target compound obtained can be isolated and purified, if necessary, by conventional methods such as recrystallization, reprecipitation or chromatography using appropriate eluent(s).
Step E6 is a step for preparing a compound (La-1) which is a compound (La) where R1 is a hydrogen atom and R2 and R3 together form a group (xe2x80x94(Cxe2x95x90O)xe2x80x94). In this step, a compound (IL) is converted into the target compound (La-1) in an inert solvent in the presence of a reducing agent.
The solvent used in the above-mentioned reaction is not particularly limited provided that it has no adverse effect on the reaction and dissolves the starting materials to some extent.
Examples of preferred solvents include alcohols such as methanol, ethanol or isopropanol; ethers such as diethyl ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran or dioxane; aromatic hydrocarbons such as benzene, toluene or xylene; aliphatic hydrocarbons such as hexane or cyclohexane; or esters such as ethyl acetate or propyl acetate. Of these solvents, alcohols are preferred.
The reducing agent used in the above reaction is not particularly limited provided that it is usually used in catalytic hydrogenations. Examples of preferred reducing agents include palladium-on-charcoal, platinum oxide, platinum black, rhodium-aluminium oxide, triphenylphosphine-rhodium chloride (Wilkinson complex), palladium-barium sulfate or Raney nickel, and palladium-on-charcoal is most preferred.
The pressure in the reduction reaction is not particularly limited, but the reaction is usually cried out at a pressure of from 1 to 10 atmospheric pressures.
The reaction temperature mainly depends on the starting material compounds, the solvent and the base employed in the reaction. The reaction is usually carried out at a temperature of from 0xc2x0 C. to 100xc2x0 C.
The reaction time mainly depends on the starting material compounds, the reaction temperature, the solvent and the base employed in the reaction. The reaction is usually carried out in a period of from 5 minutes to 48 hours.
For example, after removing the catalyst by filtration, the target compound can be obtained by concentrating the reaction mixture or conducting the following steps successively: adding an organic solvent which is not miscible with water (e.g. ethyl acetate); separating the organic layer containing the target compound; and then drying over anhydrous sodium sulfate, anhydrous magnesium sulfate or the like; and removing solvent by evaporation.
The target compound obtained can be isolated and purified, if necessary, by conventional methods such as recrystallization, reprecipitation or chromatography using appropriate eluent(s).
In Step E7, a compound (XLVII) is converted into a compound of general formula (LI) in an inert solvent in the presence of a reducing agent. This step is carried out in a similar manner to that described earlier in Step E6 of the method E.
In Step E8, a compound (La-2) which is a compound (La) where R3a is a hydrogen atom is prepared by hydrolyzing a compound (LI) in an inert solvent in the presence of a base. This step is carried out in a similar manner to that described earlier in Step E4 of the method E.
Step E9 is a step for preparing a compound (La-1), and in this step, a compound (La-2) is converted into the compound (La-1) in an inert solvent in the presence of a base. This step is carried out in a similar manner to that described earlier in Step E5 of the method E.
In Step E10, if necessary, a compound (La-3) which is a compound (La) where R2 and R3a together do not form a group (Cxe2x95x90O) is prepared by protecting a hydroxyl group of the compound (La-2). The reaction of this step depends on the nature of the hydroxyl group to be protected, but it can be carried out by the procedures, for example, described in Protective Groups in Organic Synthesis (third Edition, 1999, John Wiley and Sons, Inc.).
Alternatively, a compound (Ib-3) can be prepared by conducting the steps E2-E10 of the method E successively using a compound (XLIVb) as the starting material instead of a compound (XLIVa).
In Method F, a compound (XLVI) is synthesized. 
In the above scheme, Ar and Z are as defined earlier.
In Step F1, a compound (XLVI) is prepared by the reaction of a compound of general formula (LII) with triphenylphosphine in an inert solvent.
The inert solvent used in the above-mentioned reaction is not particularly limited provided that it has no adverse effect on the reaction. Examples of suitable solvents include aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether, aromatic hydrocarbons such as toluene, benzene or xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; or ethers such as diethyl ether, diisopropyl ether, tetrhydrofuran, dioxane, dimethoxyethane or di(ethylene glycol)dimethyl ether. Of these solvents, aromatic hydrocarbons (particularly benzene) are preferred.
The reaction temperature mainly depends on the starting material compounds and the solvent employed in the reaction. The reaction is usually carried out at a temperature of from room temperature to 200xc2x0 C., preferably from 0xc2x0 C. to 150xc2x0 C. and most preferably at 110xc2x0 C.
The reaction time mainly depends on the reaction temperature, the starting material compounds and the solvent employed in the reaction. The reaction is usually carried out in a period of from 5 minutes to 96 hours, preferably from 15 minutes to 48 hours and most preferably in 24 hours.
The product thus prepared in each step of the Method F can be, if necessary, isolated and purified by conventional techniques such as recrystallization, reprecipitation or procedures that are usually used for the isolation and purification of organic compounds. Examples of the suitable techniques include adsorption column chromatography using a stationary phase such as silica gel, alunina or florisil composed of magnesium-silica gel; partition chromatography using a synthetic adsorbent such as Sephadex LH-20 (Phamacia), Amberlite XAD-11 (Rohm and Haas) or Diaion HP-20 (Mitsubishi Chemical Company); ion-exchange chromatography; or normal and reversed phase liquid chromatography using silica gel or alkylated silica gel (preferably high performance liquid chromatography). The target compound prepared at each step is isolated and purified by any of these techniques or a suitable combination of these techniques using an appropriate solvent(s) as an eluent.
The separation of the isomers can be, if necessary, carried out by means of any of the separation/purification procedures mentioned above after the completion of the reaction of each step or at the suitable stage after the completion of the desired step.
The compounds such as (XXVIII), (XXXIV), (XLII), (XLI) and (LII) used as the starting materials are either known compounds or can be prepared easily by known or similar methods.
The aminoalcohol derivatives of the general formula (I) of the present invention, pharmacologically acceptable salts, esters or other derivatives thereof exhibit an excellent immunosuppressive effect with low toxicity. Further, pharmaceutical compositions containing the compound having the general formula (I) of the present invention or a pharmacologically acceptable salt, ester or other derivative thereof as the active ingredient are useful as preventives and/or therapeutic agents for, particularly, autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, polymyositis, dermatomyositis, scleoderma, Behcet""s disease, Chron disease, ulcerative colitis, autoimmune hepatitis, aplastic anemia, idiopathic thrombocytpenic purpura, autoimmune hemolytic anemia, multiple sclerosis, autoimmune bullosis, vulgarity psoriasis, vasculitis syndrome, Wegener""s granuloma, uveitis, cryptogenic fibrosing alveolitis, Goodpasture""s syndrome, sarcoidosis, allergic ganulomatous angitis, bronchial asthma, myocarditis, cardiomyopathy, aortic arch syndrome, myocardial postinfarction syndrome, primary pulmonar hypertension, minimal change nephrotic syndrome, membranous nephropathy, membranoproliferative glomerulonephritis, focal glomemlar sclerosis, crescent glomcrulonephritis, myasthenia gravis, inflammatory neuropathy, atopic dermatitis, chronic actinic dermatitis, acute polyarthritis, Sydenhan chorea disease, progressive systemic sclerosis, adult onset type diabetes mellitus, insulin dependent diabetes mellitus, juvenile diabetes, atherosclerosis, glomerular nephritis, tuburointrestitial nephritis, primary biliary cirrhosis, primary sclerosing cholangitis, fulminant hepatic failure, viral hepatitis, GVHD, immunological rejection following organ transplantation, contact dermatitis, sepsis, or other immunology related diseases.
In addition, the novel optically active aminoalcohol compounds such as (La) and (Lb) of the present invention are useful as intermediates for the manufacturing of the medicaments.
On the other hand, optically active 2-substituted-2-amino-1,3-propanediol monoester derivatives (XLIVa) and (XLIVb) are preferred synthetic intermediates in the production of the optically active aminoalcohol compounds (La) and (Lb) mentioned above and can be prepared easily and conveniently in a good yield by acylting selectively only one of the hydroxyl groups of the 2-substituted-2-amino-1,3-propanediol derivative (XLII) used as the starting material with a vinyl carboxylate derivative (XLIII) in the presence of lipase.
The compounds of general formula (I) of the present invention and pharmacologically acceptable salts or esters thereof can be administered for treatment or prevention of the above-mentioned diseases as a suitable dosage form, which is prepared from the compound alone or by mixing with a suitable pharmacologically acceptable excipient and/or diluent, such as tablets, capsules, granules, powders or syrups for oral administration, or injections or suppositories for parenteral administiation.
Such formulations may be prepared, according to well known techniques, using additives such as excipients, lubricants, binde; disintegrators: stabilizes, corrigents and/or diluent.
Examples of suitable excipients include organic excipients including glucose derivatives such as lactose, sucrose, glucose, mannitol and sorbitol; starch derivatives such as corn starch, potato starch, xcex1-starch and dextrin; cellulose derivatives such as crystalline cellulose; gum Arabic; dextran; and Pullulan, and inorganic excipients including silicate derivatives such as anhydrous light silicic acid, synthetic aluminium silicae, calcium silicate and magnesium metaaluminosilicate; phosphates such as calcium hydrogen phosphate; carbonates such as calcium carbonate; and sulfates such as calcium sulfate. Examples of suitable lubricants include stearic acid; metal states such as calcium steake and magnesium stearate; talc; colloidal silica; waxes such as bee gum or spermaceti; boric acid; adipic acid; sulfates such as sodium sulfate; glycol; fumaric acid; sodium benzoate; DL leucine; sodium salt of fatty acid; lauryl sulfates such as lauryl sodium sulfate or lauryl magnesium sulfate; silicates such as anhydrous silicic acid or silicic hydrate; and the above-mentioned starch derivatives.
Examples of suitable binders include hydroxyproyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, Macrogol and the compounds described above as an excipient. Examples of suitable disintegrators include cellulose derivatives such as low substituted hydroxypropylcellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose, internal-crosslinked sodium carboxymethyl cellulose; chemically modified starch-cellulose derivatives such as carboxymethyl starch, sodium carboxymethyl starch or cross-linked polyvinylpyrrolidone. Examples of suitable stabilizers include p-hydroxybenzoic esters such as methylparaben or propylparaben; alcohols such as chlorobutanol, benzyl alcohol or phenylethyl alcohol; benzalkonium chloride; phenols such as phenol or cresol; thimesal; dehydroacetic acid; and sorbic acid. Corrigents include sweetenes, souring agents and flavors that are commonly used in the art.
The dosage may vary depending on a variety of factors such as the symptoms and age of the patient and route of administration. A suitable dosage level for oral administration is from 0.05 mg (preferably 5 mg) per day as a lower limit to 200 mg (preferably 40 mg) per day as an upper limit for adults (e.g. human adults). On the other hand, a suitable dosage level for intravenous administration is from 0.01 mg (preferably 1 mg) per day as a lower limit to 100 mg (preferably 10 mg) per day as an upper limit for adults. The dosage can be administered either as a single unit dosage or, if necessary, the dosage may be divided into convenient sub-units and administered from one to six times throughout the day depending on the symptoms of the patient (e.g. human patient).